EP2134346B1 - Inhibiteurs de janus kinases et/ou protéine kinase-1 dépendant de la 3-phosphoinositide - Google Patents

Inhibiteurs de janus kinases et/ou protéine kinase-1 dépendant de la 3-phosphoinositide Download PDF

Info

Publication number
EP2134346B1
EP2134346B1 EP08726699A EP08726699A EP2134346B1 EP 2134346 B1 EP2134346 B1 EP 2134346B1 EP 08726699 A EP08726699 A EP 08726699A EP 08726699 A EP08726699 A EP 08726699A EP 2134346 B1 EP2134346 B1 EP 2134346B1
Authority
EP
European Patent Office
Prior art keywords
naphthyridin
amino
benzo
bromo
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP08726699A
Other languages
German (de)
English (en)
Other versions
EP2134346A4 (fr
EP2134346A1 (fr
Inventor
Ekaterina Kozina
Christopher Dinsmore
Tony Siu
Jonathan Young
Alan Northrup
Michael Altman
Kevin A. Keenan
David J. Guerin
Joon O. Jung
Rachel N. Maccoss
Solomon Kattar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme LLC
Publication of EP2134346A1 publication Critical patent/EP2134346A1/fr
Publication of EP2134346A4 publication Critical patent/EP2134346A4/fr
Application granted granted Critical
Publication of EP2134346B1 publication Critical patent/EP2134346B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • Janus kinase is a family of intracellular non-receptor tyrosine kinases, ranging from 120-140 kDa, that transduce cytokine-mediated signals via the JAK-STAT pathway.
  • the JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response.
  • JAK1, JAK2, JAK3 and TYK2 there are four known mammalian JAK family members: JAK1, JAK2, JAK3 and TYK2.
  • JAK1, JAK2 and TYK2 are ubiquitously expressed whereas JAK3 is expressed in the myeloid and lymphoid lineages.
  • the JAK family members are non-receptor tyrosine kinases that associate with many hematopoietin cytokines, receptor tyrosine kinases and GPCR's.
  • JAK1-/- mice were found to be developmentally similar to the JAK1+/+ although they weighed 40% less than the wild-type and failed to nurse at birth. These pups were not viable and died within 24 hours of birth ( Meraz et al Cell, 1998, 373-383 ). JAK1 deficiency led to reduced number of thymocytes, pre-B cells and mature T and B lymphocytes.
  • TYK2(-/-) mice are viable, demonstrating subtle defects in their response to IFN- ⁇ / ⁇ and IL-10 and profound defects to the response of IL-12 and LPS.
  • the breast cancer susceptibility protein acts as a tumor suppressor and contributes to cell proliferation, cycle regulation, as well as DNA damage and repair.
  • BRCA1 (-/-) mice develop normally but die by 7.5 days post embryo suggesting a key role of BRCA1 for development. Mice in which the BRCA1 protein was overexpressed led to inhibition of cell growth and sensitized cells to cytotoxic reagents.
  • Du-145 Gao FEBS Letters 2001, 488, 179-184
  • enhanced expression of BRCA1 was found to correlate with constitutive activation of STAT3 as well as activation of JAK1 and JAK2.
  • antisense oligonucleotides selective for STAT3 led to significant inhibition of cell proliferation and apoptosis in Du-145 cells. This data supports the potential utility of JAK1 and JAK2 inhibitors in the treatment of prostate cancer.
  • Asthma is a disease that is increasing in prevalence and results in "airway obstruction, airway hyperresponsiveness, and airway inflammation and remodeling” ( Pernis The Journal of Clinical Investigation 2002, 109, 1279-1283 ).
  • a common cause is the inappropriate immune responses to environmental antigens usually involving CD4+ T helper cells (TH2) which are triggered from cytokines IL-4, IL-5, IL-6, IL-10, and IL-13 which signal through JAK1/JAK3-STAT6 pathway.
  • Th1 cells are thought to be involved with the "delayed-type hypersensitivity responses" which secrete IL-2, IFN- ⁇ , and TNF- ⁇ and signal through the JAK2/TYK2-STAT4 pathway.
  • STAT6 (-/-) mice were protected from AHR when challenged with environmental antigens and showed no increase in IgE levels or the quantity of mucous containing cells.
  • JAK2 is a cytoplasmic protein-tyrosine kinase that catalyzes the transfer of the gamma-phosphate group of adenosine triphosphate to the hydroxyl groups of specific tyrosine residues in signal transduction molecules. JAK2 mediates signaling downstream of cytokine receptors after ligand-induced autophosphorylation of both receptor and enzyme.
  • the main downstream effectors of JAK2 are a family of transcription factors known as signal transducers and activators of transcription (STAT) proteins. Studies have disclosed an association between an activating JAK2 mutation (JAK2V617F) and myleoproliferative disorders.
  • the myeloproliferative disorders are clonal stem cell diseases characterized by an expansion of morphologically mature granulocyte, erythroid, megakaryocyte, or monocyte lineage cells.
  • Myeloproliferative disorders include polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), juvenile myelomonocytic leukemia (JMML) and systemic mast cell disease (SMCD). It has been suggested that abnormalities in signal transduction mechanisms, including constitutive activation of protein tyrosine kinases, initiate MPD.
  • JAK3 associates with the common gamma chain of the extracellular receptors for the following interleukins: IL-2, IL-4, IL-7, IL-9 and IL-15.
  • a JAK3 deficiency is associated with an immune compromised (SCID) phenotype in both rodents and humans.
  • SCID immune compromised
  • the SCID phenotype of JAK3 -/- mammals and the lymphoid cell specific expression of JAK3 are two favorable attributes of a target for an immune suppressant. Data suggests that inhibitors of JAK3 could impede T-cell activation and prevent rejection of grafts following transplant surgery, or to provide therapeutic benefit to patients suffering autoimmune disorders.
  • 3-Phosphoinositide-dependent protein kinase-1 is a 556-amino acid containing enzyme comprised of a C-terminal Pleckstrin homology (PH) domain (residues 459-550) and an N-terminal kinase domain (residues 70-359).
  • PH Pleckstrin homology
  • the PH domain of PDK1 binds phosphatidylinositols (e.g., phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-triphosphate) produced by phosphatidylinositol kinases, such as phosphatidylinositol 3-kinase (PI3K) and whose levels are, in part, controlled by phosphatases such as PTEN (phosphatase and tensin homologue).
  • phosphatidylinositols e.g., phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-triphosphate
  • PDK1 plays a central role in the PI3K/Akt pathway and has been called a "master regulator" kinase due to its role as a critical upstream activating kinase that phosphorylates the so-called T-loop phosphorylation site for multiple kinases in the AGC family of kinases including but not limited to all three isoforms of PKB (PKB ⁇ , PKB ⁇ , PKB ⁇ , also known as Akt1, Akt2, and Akt3, respectively), RSK (three isoforms RSK1, RSK2, RSK3, also known as p90RSK), p70S6K (two isoforms, S6K1 and S6K2), PKN (three isoforms PKN1, PKN2, and PKN3), SGK1 and PKC.
  • PKB PKB ⁇ , PKB ⁇ , PKB ⁇ , also known as Akt1, Akt2, and Akt3, respectively
  • RSK three isoforms RSK1, RSK2, RSK3,
  • PKB Protein growth factor-1
  • vascular endothelial growth factor vascular endothelial growth factor
  • PKB contains a PH domain that binds phosphatidyl 3,4,5-triphosphate.
  • PKB is translocated to the plasma membrane and phosphorylated by PDK1 at residue T-308/309 (the two phosphosites correspond to different human isoforms) in response to the second messenger phosphatidyl 3,4,5-triphosphate produced by PI3K.
  • Activation of PKB in tumor cells results in increased cellular survival via anti-apoptotic signals and also proliferation.
  • PKB ⁇ amplification has been observed in a proportion of several tumor types including ovarian, breast and pancreatic cancers. Similarly, PKB ⁇ amplification has been observed in a percentage of gastric adenocarcinoma samples. Recently, an activated mutant form of PKB ⁇ (E17K) was detected in a number of breast (8%), colorectal (6%), and ovarian (2%) cancers.
  • PDK1 kinase inhibitors are useful as treatments for diseases linked to PKB signaling (such as cancer, Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome) by preventing activation of PKB signaling by PDK1.
  • PDK1 kinase inhibitors are useful for treating cancer or other proliferative disorders by blocking the activation of p70S6K by PDK1.
  • p70S6K There are several substrates of p70S6K, such as ribosomal S6 protein, eIF4B, PDCD4 etc., that are involved in translation inhibition complex formation or ribosomal protein synthesis. Inhibition of protein synthesis via inhibition of phosphorylation of ribosomal S6 protein is believed to inhibit the proliferation of tumor cells by mTOR inhibitors (e.g., rapamycin).
  • mTOR inhibitors e.g., rapamycin
  • Hyperactivation of p70S6K (as measured by phosphorylation of T389) has been observed by immunohistochemical analysis of breast, head and neck squamous cell carcinoma (HNSCC), glioblastoma, lung and liver primary tumor specimens.
  • HNSCC head and neck squamous cell carcinoma
  • PDK1 kinase inhibitors are useful for the treatment of cancer by blocking the activation of RSK1 (also known as p90RSK) by PDK1.
  • RSK1 transduces anti-apoptotic and proliferative signals be mediating phosphorylation directly or indirectly of BAD, LKB1, TSC2, NFkB, mTOR.
  • Ras/MAPK pathway is activated in >50% of primary tumors.
  • RSK1 activity is correlated with MAPK activity.
  • RSK1 is overexpressed in primary breast and prostate cancer samples.
  • PDK1 signaling regulates multiple critical steps in angiogenesis. Inhibitors of the activity of PDK1 are thus useful in the treatment of cancer (both primary tumors and metasteses).
  • PDK1 is a key signaling molecule in cancers associated with deregulated activity of the PTEN/PI3K pathway including, but not limited to PTEN loss of function mutations, PI3K gain of function mutations and receptor tyrosine kinase gain of function mutations.
  • inhibitors of PDK1 are especially useful in the treatment of cancers with abberant signaling of the PTEN/PI3K pathway.
  • PDK1 signaling has also been implicated in tumorigenesis and a PDK1 inhibitor is useful for the tumor prevention or for the prevention of tumor recurrence.
  • Mice with a PTEN heterozygous (PTEN +/- ) genotype are well-known to spontaneously develop tumors.
  • Alessi and co-workers found that PDK1 hypomorphic PTEN +/- mice expressing ⁇ 30% of normal PDK1 protein levels showed a significant delay in tumor formation as compared to littermate controls expressing normal levels of PDK1 protein ( Current Biology, 2005, 15, 1839-1846 )
  • SGK1 serum and glucocorticoid-regulated kinase-1
  • activity is critical for insulin-mediated Na+ retention and hypertensive effects.
  • Inhibition of SGK1 activity by a PDK1 kinase inhibitor is useful in treating hypertension and/or hypoinsulinemia.
  • the instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1.
  • the invention also provides for compositions comprising such inhibitory compounds and compounds for use in methods of inhibiting the activity of JAK1, JAK2, JAK3 TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
  • One embodiment of the invention is illustrated by a compound of the following formula, and the pharmaceutically acceptable salts and stereoisomers thereof:
  • the instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1.
  • the invention also provides for compositions comprising such inhibitory compounds and compounds for use in methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
  • One embodiment of the invention is illustrated by a compound of the formula wherein D is CH, N, or NO; E is CH, N, or NO; G is CH, N, or NO; J is CH, N, or NO; R 1 is
  • D is CH.
  • E is CH. In an embodiment of the invention, E is N.
  • G is CH.
  • J is CH.
  • R 1 is
  • R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 2 is -NR 5 R 6 .
  • R 3 is hydrogen; halo or heteroaryl, which is optionally substituted on either the carbon or the heteroatom with one to three groups independently selected from C 1-6 alkyl (which is optionally substituted with one to three halo), halo or R 10 .
  • R 3 is halo or heteroaryl, which is optionally substituted on either the carbon or the heteroatom with one to three groups independently selected from C 1-6 alkyl (which is optionally substituted with one to three halo), halo or R 10 .
  • R 5 is (a) C 1-6 alkyl, which is optionally substituted with one to three substituents independently selected from halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, -NR 13 R 14 or hydroxyl; or (b) aryl, which is optionally substituted with one to three substituents independently selected from halo, C 1-6 alkyl, aryl, hydroxyl, - O(heteroaryl) or heteroaryl.
  • R 5 is C 1-6 alkyl, which is substituted with one to three substituents independently selected from halo or C 1-6 haloalkyl.
  • R 5 is C 1-6 alkyl, which is substituted with trifluoromethyl. In another subclass of the invention, R 5 is trifluoromethyl. In another class of the invention, R 5 is aryl, which is optionally substituted with one to three halo.
  • A is hydrogen
  • compositions which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier.
  • the invention is also contemplated to encompass a pharmaceutical composition which is comprised of a pharmaceutically acceptable carrier and any of the compounds specifically disclosed in the present application.
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190 ), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.
  • the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • Pyridones exist as a mixture of 1H/2H tautomers.
  • the tautomeric forms of the pyridone moiety are also within the scope of the instant invention.
  • any variable e.g. R 3 , etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents and variables are permissible only if such combinations result in stable compounds.
  • Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.
  • one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon.
  • size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off target activity, packaging properties, and so on.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the phrase "optionally substituted with one or more substituents” should be taken to be equivalent to the phrase “optionally substituted with at least one substituent” and in such cases the preferred embodiment will have from zero to four substituents, and the more preferred embodiment will have from zero to three substituents.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 10 as in “(C 1 -C 10 )alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement.
  • (C 1 -C 10 )alkyl specifically includes methyl, ethyl, n -propyl, i -propyl, n -butyl, t -butyl, i -butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • (C 2 -C 6 )alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl shall mean a substituting univalent group derived by conceptual removal of one hydrogen atom from a straight or branched-chain acyclic unsaturated hydrocarbon containing at least one triple bond (i.e., -C ⁇ CH, -CH 2 C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CCH 2 (CH 3 ) 2 , etc.).
  • cycloalkyl means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.
  • haloalkyl means an alkyl radical as defined above, unless otherwise specified, that is substituted with one to five, preferably one to three halogen. Representative examples include, but are not limited to trifluoromethyl, dichloroethyl, and the like.
  • Alkoxy represents either a cyclic or non-cyclic alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl and cycloalkyl above.
  • substituents may be defined with a range of carbons that includes zero, such as (C 0 -C 6 )alkyl-aryl. If aryl is taken to be phenyl, this definition would include phenyl itself as well as -CH 2 Ph, -CH 2 CH 2 Ph, CH(CH 3 )CH 2 CH(CH 3 )Ph, and so on.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydro-naphthyl, indanyl and biphenyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • heteroaryl represents a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • Such heteraoaryl moieties for substituent Q include but are not limited to: 2-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl and 4-isoquinolinyl.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 3-to 10-membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes the above mentioned heteroaryls, as well as dihydro and tetrathydro analogs thereof.
  • heterocyclyl include, but are not limited to the following: benzoimidazolyl, benzoimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,
  • halo or halogen as used herein is intended to include chloro (Cl), fluoro (F), bromo (Br) and iodo (I).
  • alkyl Whenever the term “alkyl,” “aryl,” “cycloalkyl,” hetercyclyl” or “heteroaryl” or either of their prefix roots appear in a name of a substituent (e.g., (C 1-6 alkyl)aryl or (C 1-6 alkyl) (C 3-6 cycloalkyl)) it shall be interpreted as including those limitations given above for “alkyl,” “aryl,” “cycloalkyl,” hetercyclyl” or “heteroaryl.” Designated numbers of carbon atoms (e.g., C 1-6 ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • a substituent e.g., (C 1-6 alkyl)aryl or (C 1-6 alkyl) (C 3-6 cycloalkyl)
  • the instant invention is the free form of compounds of the instant invention, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some of the isolated specific compounds exemplified herein are the protonated salts of amine compounds.
  • the term "free form” refers to the amine compounds in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the isolated salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds of the instant invention.
  • the free form of the specific salt compounds described may be isolated using techniques known in the art.
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • the pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods.
  • the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reacting a basic instant compound with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic (TFA) and the like.
  • inorganic acids such as hydroch
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N 1 -dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine,
  • the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • the compounds of the present invention are inhibitors of JAK 1, JAK2, JAK 3, TYK2 and PDK1, and are therefore useful to treat or prevent myeloproliferative disorders or cancer in mammals, preferably humans.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting JAK1 tyrosine kinase.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting JAK2 tyrosine kinase.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting JAK3 tyrosine kinase.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting TYK2 tyrosine kinase.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting PDK1 tyrosine kinase.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting wild type or mutant JAK2 tyrosine kinase.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting JAK2V617F tyrosine kinase.
  • Myeloproliferative disorders that may be treated include polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), juvenile myelomonocytic leukemia (JMML), and systemic mast cell disease (SMCD).
  • PV polycythemia vera
  • E essential thrombocythemia
  • MMM myeloid metaplasia with myelofibrosis
  • CML chronic myelogenous leukemia
  • CMML myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • JMML juvenile myelomonocytic leukemia
  • SMCD systemic mast cell disease
  • JAK2 JAK2-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl
  • Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac : sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal : esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcino
  • the compounds, compositions and uses of the invention may also be useful in treating the following disease states: keloids and psoriasis.
  • Cancers that may be treated by the compounds, compositions and uses of the invention include, but are not limited to: breast, prostate, colon, colorectal, lung, brain, testicular, stomach, pancrease, skin, small intestine, large intestine, throat, head and neck, oral, bone, liver, bladder, kidney, thyroid and blood.
  • Cancers that may be treated by the compounds, compositions and uses of the invention include: breast, prostate, colon, ovarian, colorectal and lung (non-small cell lung).
  • Cancers that may be treated by the compounds, compositions and uses of the invention include: breast, colon, colorectal and lung.
  • Cancers that may be treated by the compounds, compositions and uses of the invention include: lymphoma and leukemia.
  • the compounds of the instant invention are also inhibitors of the activity of PDK1 and are thus useful in the treatment of cancer, in particular cancers associated with deregulated activity of the PTEN/PI3K pathway including, but not limited to PTEN loss of function mutations, PI3h gain of function mutations and receptor tyrosine kinase gain of function mutations.
  • cancers include, but are not limited to, ovarian, pancreatic, breast and prostate cancer, as well as cancers (including glioblastoma) where the tumor suppressor PTEN is mutated. See, Feldman, Richard I., et al., "Novel Small Molecule Inhibitors of 3-Phosphoinositide-dependent Kinase-1," The Journal of Biological Chemistry, Vol. 280, No. 20, Issue of May 20, pp. 19867-19874, 2005 .
  • PDK1 signaling regulates multiple critical steps in angiogenesis. See, Mora, Alfonso et al., "PDK1, the master regulator of AGC kinase signal transduction," Seminars in Cell & Developmental Biology 15 (2004) 161-170 .
  • the utility of angiogenesis inhibitors in the treatment of cancer is known in the literature, see J. Rak et al. Cancer Research, 55:4575-4580, 1995 and Dredge et al,; Expert Opin. Biol. Ther. (2002) 2(8):953-966 , for example.
  • the role of angiogenesis in cancer has been shown in numerous types of cancer and tissues: breast carcinoma ( G. Gasparini and A.L. Harris, J. Clin.
  • cancers include, advanced tumors, hairy cell leukemia, melanoma, advanced head and neck, metastatic renal cell, non-Hodgkin's lymphoma, metastatic breast, breast adenocarcinoma, advanced melanoma, pancreatic, gastric, glioblastoma, lung, ovarian, non-small cell lung, prostate, small cell lung, renal cell carcinoma, various solid tumors, multiple myeloma, metastatic prostate, malignant glioma, renal cancer, lymphoma, refractory metastatic disease, refractory multiple myeloma, cervical cancer, Kaposi's sarcoma, recurrent anaplastic glioma, and metastatic colon cancer ( Dredge et al., Expert Opin. Biol. Ther. (2002) 2(8):953-966 ).
  • the PDK1 inhibitors disclosed in the instant application are also useful in the treatment of these angiogenesis related cancers.
  • Tumors which have undergone neovascularization show an increased potential for metastasis.
  • angiogenesis is essential for tumor growth and metastasis.
  • the PDK1 inhibitors disclosed in the present application are therefore also useful to prevent or decrease tumor cell metastasis.
  • Ocular neovascular diseases are an example of conditions where much of the resulting tissue damage can be attributed to aberrant infiltration of blood vessels in the eye (see WO 00/30651, published 2 June 2000 ).
  • the undesireable infiltration can be triggered by ischemic retinopathy, such as that resulting from diabetic retinopathy, retinopathy of prematurity, retinal vein occlusions, etc., or by degenerative diseases, such as the choroidal neovascularization observed in age-related macular degeneration.
  • Inhibiting the growth of blood vessels by administration of the present compounds would therefore prevent the infiltration of blood vessels and prevent or treat diseases where angiogenesis is implicated, such as ocular diseases like retinal vascularization, diabetic retinopathy, age-related macular degeneration, and the like.
  • a compound of the present invention for use in treating or preventing a non-malignant disease in which angiogenesis is implicated, including but not limited to: ocular diseases (such as, retinal vascularization, diabetic retinopathy and age-related macular degeneration), atherosclerosis, arthritis, psoriasis, obesity and Alzheimer's disease ( Dredge et al., Expert Opin Biol. Ther. (2002) 2(8):953-966 ).
  • ocular diseases such as, retinal vascularization, diabetic retinopathy and age-related macular degeneration
  • atherosclerosis such as, atherosclerosis, arthritis, psoriasis, obesity and Alzheimer's disease
  • a compound of the present invention for use in treating or preventing a disease in which angiogenesis is implicated includes: ocular diseases (such as, retinal vascularization, diabetic retinopathy and age-related macular degeneration), atherosclerosis, arthritis and psoriasis.
  • a compound of the present invention for use in treating hyperproliferative disorders such as restenosis, inflammation, autoimmune diseases and allergy/asthma.
  • a compound of the present invention for use in treating hypoinsulinism.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting JAK3 tyrosine kinase.
  • An embodiment of the invention provides compounds or any of the pharmaceutical compositions described above for use in inhibiting TYK2 tyrosine kinase.
  • Exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal in need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of: bone loss, bone resorption, bone fractures, metastatic bone disease and/or disorders related to cathepsin functioning.
  • the compounds of this invention may be administered to mammals, including humans, either alone or, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • topical application For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the instant invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polyactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of an inhibitor of JAK2 is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount of inhibitor of between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, or between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • Another therapeutic dosage that comprises the instant composition includes from about 0.01 mg to about 1000 mg of inhibitor of JAK2. In another embodiment, the dosage comprises from about 1 mg to about 1000 mg of inhibitor of JAK2.
  • the instant compounds are also useful in combination with therapeutic, chemotherapeutic and anti-cancer agents.
  • Combinations of the presently disclosed compounds with therapeutic, chemotherapeutic and anti-cancer agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers . A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.
  • the instant compounds are particularly useful when co-administered with radiation therapy.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylomithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signal transduction pathways, antimetabolites, biological response modifiers, hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.
  • cytotoxic/cytostatic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine,
  • hypoxia activatable compound is tirapazamine.
  • proteosome inhibitors include but are not limited to lactacystin and MLN-341 (Velcade).
  • microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, BNP
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E
  • histone deacetylase inhibitors include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A. et al. J. Med. Chem. 46(24):5097-5116 (2003 ).
  • “Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-R1.
  • PLK Polo-like kinases
  • An example of an “aurora kinase inhibitor” is VX-680.
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-dichlorophenyl)ure
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin (MEVACOR ® ; see U.S. Patent Nos. 4,231,938 , 4,294,926 and 4,319,039 ), simvastatin (ZOCOR ® ; see U.S. Patent Nos. 4,444,784 , 4,820,850 and 4,916,239 ), pravastatin (PRAVACHOL ® ; see U.S. Patent Nos.
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343 , WO 97/18813 , WO 97/21701 , WO 97/23478 , WO 97/38665 , WO 98/28980 , WO 98/29119 , WO 95/32987 , U.S. Patent No. 5,420,245 , U.S. Patent No. 5,523,430 , U.S. Patent No. 5,532,359 , U.S. Patent No. 5,510,510 , U.S. Patent No. 5,589,485 , U.S. Patent No. 5,602,098 , European Patent Publ.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- ⁇ , interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib ( PNAS, Vol.
  • NSAIDs nonsteroidal anti-inflammatories
  • NSAIDs nonsteroidal anti-
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med.
  • agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692 (2000 )).
  • agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998 )), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354 (2001 )).
  • TAFIa inhibitors have been described in U.S. Ser. Nos. 60/310,927 (filed August 8, 2001 ) and 60/349,925 (filed January 18, 2002 ).
  • Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • agents include inhibitors of ATR, ATM, the CHK11 and CHK12 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • agents that interfere with receptor tyrosine kinases refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression.
  • agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met.
  • Further agents include inhibitors of RTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001 .
  • “Inhibitors of cell proliferation and survival signalling pathway” refer to compounds that inhibit signal transduction cascades downstream of cell surface receptors. Such agents include inhibitors of serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064 , WO 02/083139 , WO 02/083140 , US 2004-0116432 , WO 02/083138 , US 2004-0102360 , WO 03/086404 , WO 03/086279 , WO 03/086394 , WO 03/084473 , WO 03/086403 , WO 2004/041162 , WO 2004/096131 , WO 2004/096129 , WO 2004/096135 , WO 2004/096130 , WO 2005/100356 , WO 2005/100344 , US 2005/029941 , US 2005/44294 , US 2005/43361 , 60/734188 , 60/652737 , 60/
  • NSAID's which are potent COX-2 inhibiting agents.
  • an NSAID is potent if it possesses an IC 50 for the inhibition of COX-2 of 1 ⁇ M or less as measured by cell or microsomal assays.
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC 50 for COX-2 over IC 50 for COX-1 evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Patent 5,474,995 , U.S. Patent 5,861,419 , U.S. Patent 6,001,843 , U.S. Patent 6,020,343 , U.S. Patent 5,409,944 , U.S. Patent 5,436,265 , U.S.
  • Patent 5,536,752 U.S. Patent 5,550,142 , U.S. Patent 5,604,260 , U.S. 5,698,584 , U.S. Patent 5,710,140 , WO 94/15932 , U.S. Patent 5,344,991 , U.S. Patent 5,134,142 , U.S. Patent 5,380,738 , U.S. Patent 5,393,790 , U.S. Patent 5,466,823 , U.S. Patent 5,633,272 and U.S. Patent 5,932,598 , all of which are hereby incorporated by reference.
  • Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpimase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene
  • integrin blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ v ⁇ 3 integrin and the ⁇ v ⁇ 5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ v ⁇ 6 , ⁇ v ⁇ 8 , ⁇ 1 ⁇ 1 , ⁇ 2 ⁇ 1 , ⁇ 5 ⁇ 1 , ⁇ 6 ⁇ 1 and ⁇ 6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3 , ⁇ v ⁇ 5 , ⁇ v ⁇ 6 , ⁇ v ⁇ 8 , ⁇ 1 ⁇ 1 , ⁇ 2 ⁇ 1 , ⁇ 5 ⁇ 1 , ⁇ 6 ⁇ 1 and ⁇ 6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the instantly claimed compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913 ; J. Biol. Chem. 1999;274:9116-9121 ; Invest.
  • PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856 ), and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy) pheny
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Patent No.
  • a uPA/uPAR antagonist (" Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8):1105-13 ), and interferon gamma ( J. Immunol. 2000; 164:217-222 ).
  • the compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • a compound of the present invention may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos.
  • neurokinin-1 receptor antagonists especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos.
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • phenothiazines for example prochlorperazine, fluphenazine, thioridazine and mesoridazine
  • metoclopramide metoclopramide or dronabinol.
  • conjunctive therapy with an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Patent Nos. 5,162,339 , 5,232,929 , 5,242,930 , 5,373,003 , 5,387,595 , 5,459,270 , 5,494,926 , 5,496,833 , 5,637,699 , 5,719,147 ; European Patent Publication Nos.
  • the neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent No. 5,719,147 .
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF).
  • G-CSF human granulocyte colony stimulating factor
  • Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • an immunologic-enhancing drug such as levamisole, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • a compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane.
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.
  • the compounds of the instant invention may also be administered in combination with ⁇ -secretase inhibitors and/or inhibitors of NOTCH signaling.
  • Such inhibitors include compounds described in WO 01/90084 , WO 02/30912 , WO 01/70677 , WO 03/013506 , WO 02/36555 , WO 03/093252 , WO 03/093264 , WO 03/093251 , WO 03/093253 , WO 2004/039800 , WO 2004/039370 , WO 2005/030731 , WO 2005/014553 , USSN 10/957,251 , WO 2004/089911 , WO 02/081435 , WO 02/081433 , WO 03/018543 , WO 2004/031137 , WO 2004/031139 , WO 2004/031138 , WO 2004/101538 , WO 2004/101539 and WO 02/47671 (including LY
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with inhibitors of Akt.
  • inhibitors include compounds described in, but not limited to, the following publications: WO 02/083064 , WO 02/083139 , WO 02/083140 , US 2004-0116432 , WO 02/083138 , US 2004-0102360 , WO 03/086404 , WO 03/086279 , WO 03/086394 , WO 03/084473 , WO 03/086403 , WO 2004/041162 , WO 2004/096131 , WO 2004/096129 , WO 2004/096135 , WO 2004/096130 , WO 2005/100356 , WO 2005/100344 , US 2005/029941 , US 2005/44294 , US 2005/43361 , 60/734188 , 60/652737 , 60/670469 .
  • a compound of the instant invention may also be useful for treating or preventing cancer in combination with PARP inhibitors.
  • a compound of the instant invention may also be useful for treating cancer in combination with the following therapeutic agents: abarelix (Plenaxis depot ® ); aldesleukin (Prokine ® ); Aldesleukin (Proleukin ® ); Alemtuzumabb (Campath ® ); alitretinoin (Panretin ® ); allopurinol (Zyloprim ® ); altretamine (Hexalen ® ); amifostine (Ethyol ® ); anastrozole (Arimidex ® ); arsenic trioxide (Trisenox ® ); asparaginase (Elspar ® ); azacitidine (Vidaza ® ); bevacuzimab (Avastin ® ); bexarotene capsules (Targretin ® ); bexarotene gel (Targretin ® ); bleomycin (Blnoxane ® ); bor
  • the scope of the instant invention encompasses the use of the instantly claimed compounds in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR- ⁇ agonists, PPAR- ⁇ agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • a compound of the instant invention in combination with radiation therapy and/or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxiccytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR- ⁇ agonists, PPAR- ⁇ agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with
  • the instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a compound of the instant invention and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint and any of the therapeutic agents listed above.
  • a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of
  • the compounds of the present invention can be prepared according to the following general schemes, using appropriate materials, and are further exemplified by the subsequent specific examples.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the illustrative Examples below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
  • Intermediate 3-1 was brominated under NBS conditions to provide bromo pyridone 3-2 .
  • This intermediate was subjected to Suzuki cross coupling conditions with a variety of boronic acids or esters.
  • Scheme 4 details a general method for derivatizing the phenyl ring of intermediate 4-1 .
  • Suzuki reaction with a variety of boronic acids and boronate esters provided intermediate 4-2 .
  • Scheme 5 shows a route for obtaining derivatives of the tricyclic scaffold.
  • Bromide 5-1 is subjected to Suzuki cross-coupling conditions to afford intermediate 5-2 .
  • This intermediate 5-2 is then chlorinated with phosphorus oxychloride to provide the dichloride 5-3 .
  • Intermediate 7-1 was converted to the triflate 7-2 by heating with N-phenylbis(trifluoromethanesulfonimide) and cesium carbonate. A Various amines were added to intermediate 7-2 with heat, and the resulting butoxy-protected intermediate 7-3 was deprotected with acid to afford pyridone 7-4 .
  • Intermediate 8-1 was converted to iodide 8-2 using an electrophilic iodine source, such as NIS in solvents such as acetic acid or acetonitrile at room temperature or elevated temperature.
  • Scheme 9 shows several general methods for derivatizing the tricyclic scaffold.
  • Intermediate 9-1 was converted to carbamate 9-2 using substituted chloroformates.
  • 9-1 was also acylated with acid chlorides in the presence of base to afford acylpiperidine 9-3 .
  • Versatile intermediate 9-1 was homologated to alkylpiperidine 9-4 via reductive amination utilizing a solid-supported hydride reagent and a substituted aldehyde.
  • 9-1 was transformed into urea 9-5 by treatment with isocyanates.
  • 9-1 was further transformed into sulfonamides 9-6 by the action of sulfonyl chlorides.
  • Scheme 10 shows several general methods for derivatizing the tricyclic scaffold wherein X-R3 is either N-R 3 or C-R 3 .
  • Iodides 10- 1 can be carbonylated in the presence of either alcohols or water to provide esters or acid 10-2 , respectively.
  • Ester or acid 10-2 can be reduced with a suitable hydride reagent such as DIBAL-H or LiAlH 4 to afford alcohol 10-3 which can be oxidized to afford aldehyde 10-4 .
  • Scheme 11 shows several general methods for derivatizing the tricyclic scaffold wherein X-R3 is either N-R 3 or C-R 3 .
  • Aldehyde 11-1 can be treated with an amine and a reducing agent, such as sodium triacetoxyborohydride to afford product 11-2.
  • aldehyde 11-1 can be treated with an organometallic reagent, such as an organomagnesium, organozinc or organolithium reagent to afford alcohol 11-3 .
  • an organometallic reagent such as an organomagnesium, organozinc or organolithium reagent to afford alcohol 11-3 .
  • aldehyde 11-1 can be transformed into an imine by the action of an amine and then treated with an organometallic reagent to afford amine 11-4.
  • Scheme 12 shows several general methods for derivatizing the tricyclic scaffold wherein X-R3 is either N-R 3 or C-R 3 .
  • Iodide 12-1 can be transformed into an organomagnesium reagent via iodo-magnesium exchange that can be used as a nucleophile to added to aldehydes (to afford alcohol 12-2 ), imines (to afford amine 12-3 ) or nitriles (to afford ketone 12-4 after acidic workup).
  • Scheme 13 shows several general methods for derivatizing the tricyclic scaffold wherein X-R3 is either N-R 3 or C-R 3 .
  • Iodide 13-1 can be alkenylated using a Heck reaction protocol to afford either or both regioisomer 13-2 and/or 13-3.
  • ketone 13-4 is provided following treatment of the intermediate vinyl ether with aqueous acid.
  • Scheme 14 shows a method for derivatizing the tricyclic core.
  • Iodide 14-1 can be treated with an alkyne, copper (I) iodide, a suitable palladium catalyst, ligand and base to afford alkyne 14-2.
  • Scheme 15 shows a method for derivatizing the tricyclic core.
  • Bromide 15-1 can be treated with a boronic acid, boronic ester, or trifluoroborate salt, a suitable palladium catalyst, ligand and base to afford 15-2.
  • Scheme 16 shows a method for derivatizing the tricyclic core.
  • Iodide 16-1 can be treated with an amine, a carbon monoxide source (either CO or MoCO 6 ), a suitable palladium catalyst, ligand and base to afford amide 16-2.
  • Scheme 17 shows primary amide cross couplings of bromide 17-1 that were performed using a modified procedure from Org. Lett, 2 (8), 1101-1104, 2000 by Buchwald et al. to provide amides 17-2.
  • Scheme 18 shows a method for the preparation of tricyclic pyridones containing substitutuent A (e.g., 18-14 ).
  • 2-chloro-6-A pyridines 18-1 are commercially available or are readily prepared from 2,6-dichloropyridine.
  • Compounds 18-1 can be converted to iodopyridine 18-6 in a five step sequence that involves formation of N-oxide 18-2, nitration to form 18-3, reduction of the nitro functionality to form aniline 18-4, protection as the butyl ether 18-5, and finally iodination with N-iodosuccinimide to form 18-6.
  • Boronic acid 18-9 can be prepared in four steps from acid 18-7 by forming the acid chloride of 18-7, amidating with and N, N-diisopropylamine to form 18-8, litiathing 18-8 with LDA and quenching with triisopropylborate. Boronic acid 18-9 and iodide 18-6 are then coupled via Suzuki reaction to form biaryl 18-10, that is then transformed into tricycle 18-11 by the action of NaHMDS. Tricycle 18-11 is chlorinated with POCl 3 to form dichloride 18-12 that is then treated with an amine to form 18-13. Monochloride 18-13 is then hydrolyzed to pyridone 18-14 using sodium acetate in acetic acid at elevated temperature.
  • Scheme 19 shows a method for derivatizing the tricyclic scaffold.
  • Dichloride 20-1 was alkylated at ambient or sub-ambient temperatures using ester enolates derived from esters and a strong base, such as NaHMDS to afford 20-2.
  • Bromide 22-1 was subjected to Suzuki cross-coupling conditions with a boronic acid or ester to afford 22-2.
  • Scheme 23 shows a general method for derivatizing the tricyclic core.
  • Bromide 23-1 was subjected to Suzuki cross-coupling conditions with a potassium trifluoroborate salt to afford 23-2 as well as a minor amount of 23-3.
  • Scheme 24 shows a general method for derivatizing the tricyclic core.
  • Bromide 24-1 was subjected to aminocarbonylation conditions using a CO source, a base, an amine or water, a ligand, and a suitable palladium source to afford 24-2 or 24-3.
  • Acid 24-3 could then be converted to amide 24-5 via an amide coupling protocol with carbonyldiimidazole.
  • Dichloride 26-1 was treated with an alcohol and base to afford ether 26-2.
  • Ether 26-2 was then transformed into pyridone 26-3 using a palladium catalyzed coupling of hydroxide to the pyridyl chloride 26-2.
  • Hydroxypyridine 27-1 was triflated to afford 27-2 that was then subjected to Suzuki cross-coupling conditions to afford 27-3.
  • 27-3 was then hydrolyzed under acidic conditions to provide pyridone 27-4.
  • 27-2 is also used with vinylboronic acids and vinyltrifluoroborate salts in Suzuki coupling conditions to provide alkenylated tricycle 27-5 that is then hydrogenated using a palladium catalyst to provide 27-6.
  • Butoxy-protected tricycle 27-6 is then deprotected under acidic conditions to afford pyridone 27-7.
  • Alkenyltricycle 28-1 is dihydroxylated using OsO 4 and NMO to afford both diol 28-2 and ketone 28-3.
  • Ketone 28-3 is then treated with an organometallic reagent (such as an organomagnesium compound) to provide alcohol 28-4.
  • Methylenic tricycle 28-5 is brominated to afford 28-6 which is treated with an amine to afford 28-7.
  • Step 1 9-bromo-1-chloro-N-[(1R)-2-methyl-1-(trifluoromethyl)propyl]benzo[c]-1,6-naphthyridin-6-amine
  • the 2-chloro pyridine was converted the pyridone following the procedure of J. Am. Chem. Soc. 2006, 128, 1094-10695 .
  • Step 1 9-bromo-1-chloro- N -[(1-methyl-1 H -pyrazol-3-yl)methyl]benzo[ c ]-1,6-naphthyridin-6-amine
  • Step 2 9-Bromo-6-[(1-methyl-1H-pyrazol-3-ytmethyl)-amino]-2H-benzo[c] [1,6]naphthyridin-1-one
  • Step 1 1-butoxypyrido[4,3 -c ]-1,6-naphthyridin-6-yl trifluoromethanesulfonate
  • Step 2 N -benzyl-1-butoxypyrido[4,3 -c ]-1,6-naphthyridin-6-amine
  • Step 3 6-(benzylamino)pyrido[4,3 -c ]-1,6-naphthyridin-1(2 H )-one
  • N-benzyl-1-butoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (90 mg, 0.251 mmol) was dissolved in hydrobromic acid (2.5 mL, 33% in acetic acid). The reaction mixture was left to stir overnight at room temperature. The reaction mixture was quenched with aqueous sodium hydrogen carbonate. The aqueous mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure.
  • Step 1 (3R)-3-[(9-fluoro-oxo-1,2-dihydrobenzo[c]1,6-naphthyridin-6-yl)amino]piperidinium chloride
  • Step 2 3- ⁇ (3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-6-yl)amino]piperidin-1-yl ⁇ -3-oxopropanenitrile
  • Step 1 4-bromo-6- ⁇ [(1R)-1,2-dimethylpropyl]amino ⁇ -9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one
  • Step 2 6- ⁇ [(1R)-1,2-dimethylpropyl]amino ⁇ -9-fluoro-4-(3-thienyl)benzo[c]-1,6-naphthyridin-1(2H)-one
  • Nitric acid (0.271 mL, 4.24 mmol) was added to 9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (397 mg, 1.061 mmol) in TFA (10.600 mL) at room temperature. Reaction was then heated to 40°C and stirred for 1.5 h. The reaction was then diluted with dichloromethane (150 mL) and quenched by pouring cautiously into saturated NaHCO 3 . The layers were separated and the aqueous phase was further extracted with a 75 mL portion of dichloromethane.
  • the suspension was degassed by subsurface bubbling of nitrogen for 5 minutes.
  • the reaction was then heated to 60°C under nitrogen for 24h.
  • the reaction was then diluted with ethyl acetate (150 mL) and washed with 0.1N HCl and the brine.
  • the organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was purified by column chromatography on silica gel eluting with EtOAc/Hexanes to afford the title compound as a white solid.
  • the cap on the vial was removed and the atmosphere changed to carbon monoxide by pressurizing to 30 psi and releasing the pressure 3 times inside a stainless steel pressure vessel. Then, the pressure of CO was adjusted to 100 psi and heated to 100°C for 5h. Then, the reaction was cooled to room temperature, the reaction was then poured into ethyl acetate, washed with saturated NaHCO 3 , brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water + 0.05% TFA, to afford the title compound as a white solid.
  • the reaction mixture was then added to a separatory funnel containing 3:1 CHCl 3 :2-propanol and saturated aqueous NaHCO 3 .
  • the phases were separated, and the organic layer was washed with water, then brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo.
  • the crude product mixture was purified by silica gel chromatography (0-10% CH 3 OH in CH 2 Cl 2 ), followed by trituration with methanol afforded the title compound 4-(cyclopropylethynyl)-9-fluoro-6-[( trans -3-fluoropiperidin-4-yl)aminolbenzo[ c ]-1,6-naphthyridin-1(2H)-one.
  • the reaction was purged with argon (subsurface bubbling) for 10 min.
  • the reaction mixture was heated in a microwave oven at 130°C for 45 min.
  • the mixture was then cooled to room temperature and diluted with DMSO ( ⁇ 17 mL) and filtered through a syringe filter (filter was rinsed with DMSO).
  • This solution was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water + 0.05% TFA.
  • the fractions were combined, neutralized with NaHCO3 (sat) and extracted with dichloromethane (2 x 300 mL).
  • Step 1 4-(cydopropylethynyl)-6-([(1 R )-1,2,2-trimethylpropyl]amino ⁇ benzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • Dioxane 2000 ⁇ l was added followed by Hunig's base (34.9 ⁇ l, 0.200 mmol) and degassed for 10 min with subsurface N 2 bubbling. The reaction flask was then sealed and heated to 100°C for 2 h.
  • 6-(1-benzyl-1H-pyrazol-4-yl)-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one was prepared using the same procedure as example 9-fluoro-6-(1H-indol-3-yl)benzo[c]-1,6-naphthyridin-1(2H)-one.
  • LRMS (ESI) calc'd for (C 22 H 16 FN 4 O) [M+H] + , 371.1; found 371.1
  • 2-chloro-6-methylpyridin-4-amine 36 g, 0.25 mol
  • sodium hydroxide 24 g, 1 mol
  • the reaction mixture was diluted with water (300 mL) and then extracted with ethyl acetate (3 ⁇ 500 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated to afford 2-butoxy-6-methylpyridin-4-amine.
  • Step 7 ⁇ 5-bromo-2-[(diisopropylamino)carbonyl]phenyl ⁇ boronic acid
  • Step 8 2-(4-amino-2-butoxy-6-methylpyridin-3-yl)-4-bromo- N,N -diisopropylbenzamide
  • Step 9 9-bromo-1-butoxy-3-methylbenzo[ c ]-1,6-naphthyridin-6(5 H )-one
  • Step 10 9-bromo-1,6-dichloro-3-methylbenzo[ c ]-1,6-naphthyridine
  • Step 11 9-bromo-1-chloro-3-methyl-N-(pyridin-2-ylmethyl)benzo[ c ]-1,6-naphthyridin-6-amine
  • Step 12 9-bromo-3-methyl-6-[(pyridin-2-ylmethyl)amino]benzo[ c ]-1,6-naphthyridin-1(2H)-one
  • Step 1 tert butyl 2-(9-bromo-1-chlorobenzo[ c ]-1,6-naphthyridin-6-yl)-2-methylpropanoate
  • Step 2 9-bromo-6-isopropylbenzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • Tetrahydro-2 H -pyran-4-carboxylic acid (10 g, 77 mmol) and EDC (17.68 g, 92 mmol) were added to a flask, followed by DCM (200 ml).
  • DCM 200 ml
  • Et 3 N (16 ml, 115 mmol
  • tBuOH (16.1 ml, 169 mmol
  • DMAP 9.39 g, 77 mmol
  • the reaction mixture was stirred at 40 °C for 18 hr.
  • the reaction mixture was diluted with DCM (100 M1) and washed with 1N NaOH (1 x 100 Ml) followed by 1M citric acid solution (1 x 100 M1).
  • reaction mixture was heated in a microwave reactor at 100 °C for 30 min.
  • the reaction mixture was diluted with MeOH and purified directly by preparative reverse phase HPLC eluting with an acetonitrile/water (with 0.05 % TFA modifier) gradient to afford 6-isopropyl-9-(1-methyl-1H-pyrazol-4-yl)benzo[ c ]-1,6-naphthyridin-1(2 H )-one.
  • reaction mixture was cooled to room temperature, diluted with ACN and DMF, and purified directly by preparative reverse phase HPLC, eluting with an acetonitrile/water (with 0.05 % TFA as a modifier) gradient, to afford 6-isopropyl-9-(morpholin-4-ylmethyl)benzo[ c ]-1,6-naphthyridin-1(2 H )-one as the major product, along with 6-isopropylbenzo[ c ]-1,6-naphthyridin-1(2 H )-one as the minor product.
  • the resulting suspension was purged with argon (subsurface bubbling) for 5 min.
  • the reaction mixture was stirred at 100°C for 16 hr in a sealed vial.
  • the reaction mixture was diluted with ACN, MeOH, and DMSO and purified directly by preparative reverse phase HPLC, eluting with an acetonitrile/water (0.05% TFA modifier) gradient to afford 6-isopropyl-9-(morpholin-4-ylcarbonyl)benzo[ c ]-1,6-naphthyridin-1(2H)-one.
  • Example 396 was isolated as a side product in the preparation of Example 395.
  • Table 20 Ex. Structure Name LRMS 394 9-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-6-isopropylbenzo[ c ]-1,6-naphthyridin-1 (2H)-one Calc'd 400.1, found 400.1 395 6-isopropyl- N,N -dimethyl-1-oxy-1,2-dihydrobenzo[ c ]-1,6-naphthyridine-9-carboxamide Calc'd 310.2, found 310.1 396 6-isopropyl-1-oxo-N-[3-(2-oxoazepan-1-yl)propyl]-1,2-dihydrobenzo[c]-1,6-naphthyridine-9-carboxamide Calc'd 435.2, found 43
  • Example 396 1 H NMR (500 MHz, CDCl 3 ) ⁇ 11.88 (s, 1H), 10.60 (s, 1H), 8.34 (d, 1H), 8.21 (overlapping m, 2H), 7.58 (t, 1H), 6.88 (d, 1H), 3.98 (m, 1H), 3.57 (t, 2H), 3.51 (q, 2H), 3.29 (dd, 2H), 2.54 (dd, 2H), 1.83 (m, 2H), 1.71-1.62 (overlapping m, 6H), 1.46 (d, 6H)
  • Step 1 6-isopropyl-1-oxo-1,2-dihydrobenzo[ c ]-1,6-naphthyridine-9-carboxylic acid
  • Step 2 6-isopropyl-1-oxo-1,2-dihydrobenzo[ c ]-1,6-naphthyridine-9-carboxamide
  • Step 1 1-chloro-6-isopropyl-9-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[c]-1,6-naphthyridine
  • Step 2 6-isopropyl-9-(5-methyl-1,3,4-oxadiazol-2-yl)benzo [ c ]-1,6-naphthyridin-1(2 H )-one
  • Step 1 9-bromo-4-iodo-6-isopropylbenzoI[ c ]-1,6-naphthyridin-1(2 H )-one
  • Step 2 3-(9-bromo-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl)prop-2-ynamide
  • reaction mixture was diluted with DMF and purified directly by reverse phase preparative HPLC using an acetonitrile/water (with 0.05 % TFA as a modifier) gradient to afford 3-(9-bromo-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphthyridin-4-yl)prop-2-ynamide.
  • the resulting suspension was purged with argon (subsurface bubbling) for 10 min, then heated in a microwave reactor at 100°C for 30 min.
  • the mixture was cooled, diluted with DMF, and filtered to remove salts.
  • the solution was purified directly by preparative reverse phase HPLC eluting with an acetonitrile/water (with 0.05% TFA as a modifier) gradient, to afford 3-[6-isopropyl-9-(1-methyl-1 H -pyrazol-4-yl)-1-oxo-1,2-dihydrobenzo[ c ]-1,6-naphthyridin-4-yl]prop-2-ynamide.
  • the resulting suspension was heated to 45 °C and stirred for four hours.
  • the reaction mixture was diluted with 4 mL DMF and 100uL TFA , then purified directly by preparative reverse phase HPLC eluting with an acetonitrile/water gradient (with 0.05% TFA as a modifier) to afford 9-bromo-4-(pyridin-3-ylethynyl)-6-(tetrahydro-2 H -pyran-4-yl)benzo[ c ]-1,6-naphthyridin-1(2 H )-one.
  • Step 1 1-chloro-9-fluoro-6-isopropoxybenzo[ c ]-1,6-naphthyridine
  • Step 2 9-fluoro-6-isopropoxybenzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • the reaction mixture was heated to 100°C and stirred for 16 h. After cooling to room temperature, the reaction mixture was added to saturated aqueous ammonium chloride (40 mL). The aqueous layer was extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated to a crude residue.
  • the crude material was purified by preparative reverse phase HPLC eluting with an acetonitrile/water (with 0.05% TFA as a modifier) gradient, to afford 9-fluoro-6-isopropoxybenzo[ c ]-1,6-naphthyridin-1(2 H )-one.
  • Step 1 9-bromo-1-chloro-6-isopropoxybenzo[ c ]-1,6-naphthyridine
  • Step 2 9-hydroxy-6-isopropoxybenzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • Step 1 9-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • 9-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[ c ]-1,6-naphthyridin-1(2 H )-one was prepared from 9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[ c ]-1,6-naphthyridin-1(2 H )-one utilizing a procedure found in the following reference: Klapars, A.; Buchwald, S.L. J. Am. Chem. Soc. 2002, 14844-14845 .
  • reaction mixture was heated to 130°C, and stirred for 22 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (40 mL) and brine (40 mL). The organic layer was washed with additional brine (1 x 40 ml). The first aqueous layer was back-extracted with ethyl acetate (1 x 40 mL). The combined organics were dried over sodium sulfate, filtered and concentrated.
  • Step 2 9-(metbylsulfonyl)-6-[(1,2,2-trimethylpropyl)amino]benzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • 9-(methylsulfonyl)-6-[(1,2,2-trimethylpropyl)amino]benzo[ c ]-1,6-naphthyridin-1(2 H )-one was prepared from 9-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[ c ]-1,6-naphthyridin-1(2 H )-one utilizing a procedure found in the following reference: Zhu, W.; Ma, D. J Org. Chem. 2005, 70, 2696-2700 .
  • Step 1 1-butoxy-9-fluorobenzo[ c ]-1,6-naphthyridin-6-yl trifluoromethanesulfonate
  • the organic layer was dried over sodium sulfate, filtered, and concentrated to a crude residue that was adsorbed on to silica gel.
  • the solid mixture was purified by column chromatography on silica gel eluting with an EtOAc/hexanes gradient to afford 1-butoxy-9-fluorobenzo[ c ]-1,6-naphthyridin-6-yl trifluoromethanesulfonate contaminated with approximately an equimolar amount of unreacted N-phenylbis(tifluoromethansulfonimide).
  • the level of this impurity can be reduced if necessary by using the following procedure:
  • Step 2 1-butoxy-9-fluoro-6-isopropenylbenzo[ c ]-1,6-naphthyridine
  • 1-butoxy-9-fluorobenzo[ c ]-1,6-naphthyridin-6-yl trifluoromethanesulfonate (1.00 g, 2.39 mmol), potassium phosphate tribasic (1.52 g, 7.17 mmol), palladium(II) acetate (0.0540 g, 0.239 mmol), and tricyclohexylphosphine (0.134 g, 0.478 mmol) were combined in pressure vessel.
  • Toluene (20 ml), water (6.67 ml), and isopropenylboronic acid pinacol ester (0.899 ml, 4.78 mmol) were added.
  • Step 3 9-fluoro-6-isopropenylbenzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • Step 1 1-butoxy-9-fluoro-6-isopropylbenzo[ c ]-1,6-naphthyridine
  • Step 2 9-fluoro-6-isopropylbenzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • Step 1 1-(1-butoxy-9-fluorobenzo[ c ]-1,6-naphthyridin-6-yl)ethanone
  • Step 2 2-(1-butoxy-9-fluorobenzo[ c ]-1,6-naphthyridin-6-yl)propan-2-ol
  • Step 3 9-fluoro-6-(1-hydroxy-1-methytethyl)benzo[ c ]-1,6-naphthyridin-1(2 H )-one (HBr salt)
  • Step 1 2-(1-butoxy-9-fluorobenzo[ c ]-1,6-naphthyridin-6-yl)propane-1,2-diol
  • Step 2 6-(1,2-dihydroxy-l-methylethyl)-9-fluorobenzo[ c ]-1,6-naphthyridin-1(2 H )-one (HCl salt)
  • Step 1 6-(2-bromo-1-methylethyl)-9-fluorobenzo[ c ]-1,6-naphthyridin-1(2 H )-one (HBr salt)
  • Step 2 9-fluoro-6-(1-methyl-2-morpholin-4-ylethyl)benzo[ c ]-1,6-naphthyridin-1(2 H )-one
  • 100 mg of 9-bromo-6- ⁇ [(1R)-2-methyl-1-(trifluoromethyl)propyl]amino ⁇ benzo[c]-1,6-naphthyridin-1(2H)-one is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.
  • reactions contained 5X IVGN buffer (50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml BSA), 2mM DTT, 2.0 ⁇ M peptide substrate, 25 ⁇ M MgATP, 400 pM JAK1 enzyme and subject compound in 5% DMSO. Reactions were incubated for 60 min at RT and quenched with 50 uL 2X quench detect buffer (10 mM EDTA, 25 mM HEPES, 0.1% TRITON X-100, 4.7 uM Europium-Py20 and 2.1 mg/mL streptavidin-APC).
  • 5X IVGN buffer 50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml BSA
  • 2mM DTT 2.0 ⁇ M peptide substrate
  • Peptide substrate is amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH2 (SEQ. ID NO.: 1); in DMSO.
  • the kinase activity was measured using a modified version of the homogeneous time-resolved tyrosine kinase assay described in Park et al. Anal. Biochem. 269, 94-104 (1999 ).
  • the procedure for determining the potency of a compound to inhibit JAK2 kinase comprises the following steps:
  • IC 50 was obtained by fitting the observed relationship between compound/inhibitor concentration and HTRF signal with a 4-parameter logistic equation.
  • Compounds of the instant invention are potent inhibitors of recombinant purified JAK2 kinase activity with an IC 50 of approximately 0.1 nM - 20 ⁇ M.
  • reactions contained 5X IVGN buffer (50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml BSA), 2mM DTT, 2.0 ⁇ M peptide substrate, 25 ⁇ M MgATP, 400 pM JAK3 enzyme and subject compound in 5% DMSO. Reactions were incubated for 60 min at RT and quenched with 50 uL 2X quench detect buffer (10 mM EDTA, 25 mM HEPES, 0.1% TRITON X-100, 4.7 uM Europium-Py20 and 2.1 mg/mL streptavidin-APC).
  • 5X IVGN buffer 50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml BSA
  • 2mM DTT 2.0 ⁇ M peptide substrate
  • Peptide substrate is amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH2 (SEQ. ID NO.: 1); in DMSO.
  • reactions contained 5X IVGN buffer (50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml BSA), 2mM DTT, 2.0 ⁇ M peptide substrate, 15 ⁇ M MgATP, 125 pM enzyme and subject compound in 5% DMSO. Reactions were incubated for 60 min at RT and quenched with 50 uL 2X quench detect buffer (10 mM EDTA, 25 mM HEPES, 0.1% TRITON X-100, 4.7 uM Europium-Py20 and 2.1 mg/mL streptavidin-APC).
  • 5X IVGN buffer 50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml BSA
  • 2mM DTT 2.0 ⁇ M peptide substrate
  • 15 ⁇ M MgATP
  • Peptide substrate is amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH2 (SEQ. ID NO.: 1); in DMSO.
  • JAK family kinase expression JAK3, TYK2 and JAK2 kinase domains with N-terminal "Flag" affinity tags were expressed in Sf9 cells using standard baculovirus methods.
  • the human JAK3 gene and the human TYK2 gene can be purchased from Update (now part of Millpore Corporation).
  • Human JAK2 kinase domain was cloned from a MOLT4 cDNA library (Clonetech).
  • Tyrosine kinase activity was measured by detection of the tyrosine phosphorylated peptide amino hexanoyl biotin-EQEDEPEGDYFEWLE-NH 2 (SEQ. ID NO.: 1); (S, hereafter) detected by time-resolved fluorescence using a europium labeled antibody to phosphotyrosine (pY20).
  • the JAK3(JH1) catalyzed phosphorylation reactions were carried out in a 30uL total reaction volume. The compound was run at 5% DMSO and preincubated with enzyme buffer (EB).
  • the EB comprised Invitrogen 5X kinase buffer (50 mM Hepes, pH 7.5, 10 mM MgCl 2 , 0.01% Brij-35, 1 mM EGTA, 0.1 mg/ml BSA), 2mM (final) DTT, 2 ⁇ M (final) S, and 250pM (final) JAK3 enzyme.
  • the assay was run at ATP K m (5 ⁇ M final) for 40 to 80 minutes.
  • Reactions were run at ambient temperature and quenched with an equal volume of quench buffer (QB) (10 mM EDTA, 25 mM HEPES, 0.1% TRITON X-100) containing 50 ⁇ g/mL SA•APC conjugate and 0.75 nM Eu•K conjugated pY20.
  • QB quench buffer
  • the data was analyzed by using a standard 4P fit on the ratio of the Em results: (EM 1 ⁇ EM 2 )* 10,000.
  • JAK2 When JAK2 is activated and dimerized, it phosphorylates STAT5 which translocates to the nucleus and actives the transcription of target genes.
  • AlphaScreenTM SureFireTM p-STAT5 assay (Perkin Elmer and TGR Biosciences) uses both biotinylated anti- phospho- STAT5 antibody, which is captured by Streptavidin-coated Donor beads, and anti- total STAT5 antibody, which is captured by Protein A conjugated Acceptor beads.
  • the irf1- bla HEL CellSensorTM cell line was created by transducing parental HEL 92.1.7 cells (ATCC) with the pLenti- bsd /irf1- bla CellSensorTM vector.
  • a photosensitizer in the donor bead converts ambient oxygen to a more excited singlet state.
  • the singlet state oxygen molecules diffuse across to react with a chemiluminescer in the acceptor bead that further activates flurophores contained within the same bead.
  • the fluorophores subsequently emit light at 520-620 nm.
  • the emitted light intensity is directly proportional to the amount of phospho-STAT5 proteins released from HEL irf1- bla cells.
  • Make detection reagent mixture A by adding together 800 uL reaction buffer, 20 uL acceptor beads, and 200 uL activation buffer. Add 15 uL/well of detection mixture A to the cell plates and gently agitate the plates for 1-2 min. Seal the plates with an adhesive cover and incubate at room temperature for 2 hr, avoiding exposure to light.
  • Make detection mixture B by adding together 400 uL dilution buffer and 20 uL donor beads. Add 6 uL/well of mixture B to the cell plates and gently agitate the plates for 1-2 min. Seal the plates with an adhesive cover and incubate at room temperature for 2 hr, avoiding exposure to light. Read the plates on an AlphaScreen-capable plate reader.
  • Compounds of the instant invention are potent inhibitors of pSTAT5 in the HEL irf1- bla AlphaScreenTM SureFireTM p-STAT5 Assay activity with an IC 50 of ⁇ 250 nM.
  • Cellular proliferation assays CTLL-2 cells (ATCC) were maintained in 6% T-stim Culture Supplement (source of IL2) in RPMI-1640 supplemented with 10% fetal bovine serum, 1 mM sodium pyruvate, 50 ⁇ M ⁇ -mercaptoethanol, 1.4 mM L-glutamine, 10 mM HEPES, 1 mg/ml dextrose, 0.04 mM essential amino acids, 0.02 mM nonessential amino acids, penicillin and streptomycin (H10).
  • Compounds of the instant invention are potent inhibitors of recombinant purified JAK3 kinase activity with an IC 50 of approximately 0.1 nM - 20 ⁇ M.
  • Activated recombinant full-length mT(Glu-Glu-Phe) tagged human PDK1 is used to determine whether the compounds of the instant invention modulate the enzymatic activity of this kinase.
  • the cDNA, encoding full-length PDK1 is subcloned into a baculovirus expression vector pBlueBac4.5 (Invitrogen), containing an in frame middle T tag (MEYMPME) at its N-terminus.
  • Soluble activated recombinant full-length mT(Glu-Glu-Phe) tagged human PDK1 is expressed in a baculovirus-infected Sf9 insect cells (Kemp Biotechnologies), according to the protocol recommended by the manufacturer.
  • Immunoaffinity purification of the PDK1 kinase from the insect cell lysate is performed using a middle Tag antibody bound to Protein G-EE column.
  • fractions containing PDK1 protein are pooled together, based on SDS-PAGE and western blot analyses, and then analyzed for protein concentration using BCA Protein Assay (Pierce) with BSA as standard. The final product was aliqouted and flash frozen in liquid nitrogen before being stored at -80°C. Resulting PDK1 protein has MW of 64 kDa, is phosphorylated 'by default' and purifies as an activated kinase from insect cells.
  • the procedure for determining the potency of a compound to inhibit PDK1 kinase comprises the following steps:
  • the compounds 1 to 419 in the Examples were tested in the above assay and found to have an IC 50 ⁇ 50 ⁇ M.
  • PC-3 cells grown in Earle's MEM with 10% FBS, 1X L-Glutamine, 1X Non Essential Amino Acids, 1X NaPyruvate and 1X Hepes. Other cells may be used.
  • Compounds of the instant invention are potent inhibitors of recombinant purified JAK3 kinase activity with an IC 50 of approximately 0.1 nM - 20 ⁇ M.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)

Claims (12)

  1. Composé de la formule I
    Figure imgb0466
     où D est CH, N ou NO;
    E est CH, N ou NO;
    G est CH, N ou NO;
    J est CH, N ou NO;
    R1 est
    (a) hydrogène;
    (b) alkyle C1-6, qui est optionnellement substitué par halo, hydroxyle, cycloalkyle C3-6, amino, phényle, hétérocyclyle, alkyle C1-6 ou R10 ;
    (c) alcényle C1-6, qui est optionnellement substitué par halo, hydroxyle, amino, phényle, hétérocyclyle ou alkyle C1-6 ;
    (d) alcynyle C1-6, qui est optionnellement substitué par un à deux substituants sélectionnés indépendamment parmi halo, hydroxyle, amino, phényle (qui est optionnellement substitué par alkyle C1-6), hétéroaryle (qui est optionnellement substitué par alkyle C1-6 ou O(alkyle C1-6), hétérocyclyle, alkyle C1-6, cycloalkyle C3-6, (C=O)NR13R14, NR13R14 ou Si(CH3)3;
    (e) cycloalkyle C3-10, qui est optionnellement substitué par alkyle C1-6, OR13, NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, OR13 ou NR13R14), halo, R10 ou hétérocyclyle ;
    (f) -(C=O)R13 ;
    (g) -(C=O)OR13 ;
    (h) -SOmR13 ;
    (i) -(CO)NR13NR14 ;
    (j) -(C=O)NHR13 ;
    (k) -(C=O)NR13NHR9 ;
    (l) hétérocyclyle C4-10, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par alkyle C1-6, halo, R10, -OR13, -NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, -OR14 ou -NR13R14), -(C=O)R9 ou - (C=O)NR13R14 ;
    (m) -OR13 ;
    (n) -NR13R14 ;
    (o) NO2 ;
    (p) halo;
    (q) cyano;
    (r) aryle, qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), O(alkyle C1-6), halo ou R10 ;
    (s) hétéroaryle, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), halo ou R10 ;
    (t) -O(aryle), qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6, halo ou R10 ; ou
    (u) -O(alkyle C1-6), qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6, halo ou R10 ;
    R2 est NR5R6, CR4R6R7, SR5, OR5, alcényle C1-6, cycloalkyle C3-6 (qui est optionnellement substitué par un ou deux halo), hétéroaryle ou hétérocyclyle, où lesdits groupes hétéroaryle ou hétérocyclyle sont optionnellement substitués sur le carbone ou sur l'hétéroatome par un à trois substituants sélectionnés indépendamment parmi R8 ;
    R3 est
    (a) hydrogène;
    (b) alkyle C1-6, qui est optionnellement substitué par halo, hydroxyle, amino, phényle, hétérocyclyle, alkyle C1-6 ou R10 ;
    (c) alcényle C1-6, qui est optionnellement substitué par halo, hydroxyle, amino, phényle, hétérocyclyle ou alkyle C1-6 ;
    (d) alcynyle C1-6, qui est optionnellement substitué par un ou deux substituants sélectionnés indépendamment parmi halo, hydroxyle, amino, phényle (qui est optionnellement substitué par alkyle C1-6), hétérocyclyle, hétéroaryle, alkyle C1-6 ou Si(CH3)3 ;
    (e) cycloalkyle C3-10, qui est optionnellement substitué par alkyle C1-6, -OR13, - NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, -OR13 ou -NR13R14), halo, R10 ou hétérocyclyle;
    (f) -(C=O)R11 ;
    (g) -(C=O)NR9R13 ;
    (h) -(C=O)NHNH(C=O)R11 ;
    (i) hétérocyclyle C4-10, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par alkyle C1-6, halo, R10, -OR13, -NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, OR13 ou NR13R14), -(C=O)R9 ou - (C=O)NR13R14 :
    (j) -OR13 ;
    (k) -NH(C=O)R11 ;
    (l) halo;
    (m) aryle, qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo, cyano ou hétérocyclyle), halo, hétérocyclyle ou R10 ;
    (n) hétéroaryle, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo ou hydroxy), halo, hétérocyclyle, R10 ou R11 ;
    (o) -O(aryle), qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6, halo ou R10 ;
    (p) -O(alkyle C1-6), qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6, halo ou R10 ;
    (q) -SOm(alkyle C1-6) ; ou
    (r) -SOm(aryle) ;
    R4 est
    (a) hydrogène;
    (b) alkyle C1-6, qui est optionnellement substitué par halo, hydroxyle, amino, aryle ou hétérocyclyle ;
    R5 est
    (a) hydrogène;
    (b) alkyle C1-6, qui est optionnellement substitué par un à trois substituants sélectionnés indépendamment parmi halo, cyano, alkyle C1-6, cycloalkyle C3-10, haloalkyle C1-6, aryle, -NR13R14, Si(CH3)3, SOm(alkyle C1-6), -(C=O)OR13, OR13 ou hydroxyle;
    (c) cycloalkyle C3-10, qui est optionnellement substitué par un à trois substituants sélectionnés indépendamment parmi halo, aryle (alkyle C1-6)OH ou alkyle C1-6 ;
    (d) aryle, qui est optionnellement substitué par un à trois substituants sélectionnés indépendamment parmi halo, alkyle C1-6, aryle, hydroxyle, O(hétéroaryle), haloalkyle C1-6 ou hétéroaryle;
    (e) hétéroaryle;
    (f) (alkyle C1-6)(aryle), qui est optionnellement substitué sur les groupes alkyle et aryle par un à trois substituants sélectionnés indépendamment parmi halo, cyano, alkyle C1-6, haloalkyle C1-6, cycloalkyle C3-10 ou O(alkyle C1-6) ;
    (g) (alkyle C1-6)(hétéroaryle), qui est optionnellement substitué sur les groupes alkyle et hétéroaryle par un à trois substituants sélectionnés indépendamment parmi halo, haloalkyle C1-6 ou alkyle C1-6 ;
    (h) (alkyle C1-6)(hétérocyclyle) ;
    (i) -SOm(hétérocyclyle) ;
    (j) -SOmNR7R13 ;
    (k) hétérocyclyle, qui est optionnellement substitué par un à quatre substituants sélectionnés indépendamment parmi halo, R7, (alkyle C1-6)R7, (C=O)R7, -(C=O)OR7, (C=O)NHR7, (SOm)R9 ;
    (l) (alkyle C1-6)(cycloalkyle C3-10), qui est optionnellement substitué sur l'alkyle par aryle;
    (m) alkyle C1-6(C=O)OH ;
    R6 est
    (a) hydrogène;
    (b) alkyle C1-8, qui est optionnellement substitué par un à trois substituants sélectionnés indépendamment parmi halo, hydroxyle, cyano, amino, aryle (qui est optionnellement substitué par un à trois halo), hétéroaryle, cycloalkyle, hétérocyclyle, - SO2NR13R14 ou -NR13R14 ;
    (c) cycloalkyle C3-10, qui est optionnellement substitué par halo, alkyle C1-6, haloalkyle, (alkyle C1-6)aryle, (alkyle C1-6)OR9, -OR13, -NR13R14 ou phényle (qui est optionnellement substitué par alkyle C1-6, -OR13, NR13R14, hétérocyclyle, -(CO)R9 ou - (CO)-NR13R14) ;
    R7 est
    (a) hydrogène;
    (b) alkyle C1-6, qui est optionnellement substitué par halo, cyano, hydroxyle, amino, aryle (qui est optionnellement substitué par halo, alkyle C1-6, O(alkyle C1-6) ou NR8R9), hétérocyclyle, cycloalkyle C3-10, haloalkyle C1-6, NH(C=O)R13, SOmNR13R14 ou NR13R14 ;
    (c) cycloalkyle C3-10, qui est optionnellement substitué par un à trois substituants sélectionnés indépendamment parmi halo, hydroxyle, alkyle C1-6, haloalkyle C1-6, -OR4, - NR8R4 ou phényle (qui est optionnellement substitué par alkyle C1-6, -OR4, -NR8R4, hétérocyclyle, -(CO)R8 ou -(CO)NR8R9) ;
    (d) hétérocyclyle C4-10, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à trois substituants sélectionnés indépendamment parmi halo, alkyle C1-6, -OR13, -NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, -OR13, - NR13R14, hétérocyclyle, -(CO)R9 ou -(CO)-NR13R14) ;
    (e) aryle, qui est optionnellement substitué par un à trois substituants sélectionnés indépendamment parmi halo, NR13R14 ou haloalkyle C1-6 ;
    (f) hétéroaryle qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par NR13R14 ;
    R8 est hydrogène, alkyle C1-6, (alkyle C1-6)aryle, (alcényle C1-6)aryle, (alkyle C1-6)OR9, -OR13, -NR13R14, -(CO)NR13R14, hétérocyclyle ou phényle (qui est optionnellement substitué par alkyle C1-6, -OR13, -NR13R14, hétérocyclyle, -(CO)R9 ou - (CO)-NR13R14) ;
    R9 est hydrogène, alkyle C1-6, (alkyle C1-6)aryle, (alkyle C1-6)hétérocyclyle, hétéroaryle, hétérocyclyle, cycloalkyle C3-6 ou -NR13NR14 ;
    R10 est
    (a) hydrogène;
    (b) -OR11 ;
    (c) -O(haloalkyle C1-6) ;
    (b) -CO2R11 ;
    (c) -(C=O)R11 ;
    (d) -NHR11 ;
    (e) -NR11R12 ;
    (f) -NHS(O)2R11 ;
    (g) -NH(C=O)R11 ;
    (h) -NH(C=O)OR11 ;
    (i) -NH(C=O)(NH)NH2 ;
    (j) -NH(C=O)NH2 ;
    (k) -NH(C=O)NHR11 ;
    (l) -NH(C=O)NR11R12 ;
    (m) -NHcycloalkyle C3-6 ;
    (n) -(C=O)NHR11 ;
    (o) -(C=O)NR11R12 ;
    (p) -SO2NHR11 ;
    (q) -SO2NH(C=O)R12 ; ou
    (r) -SO2R11 ;
    (s) hétérocyclyle;
    R11 est sélectionné parmi le groupe consistant en:
    (a) hydrogène,
    (b) cycloalkyle C3-6, qui est optionnellement substitué par aryle, hétéroaryle ou un à cinq halo;
    (c) alkyle C1-6, qui est optionnellement substitué par aryle, hétéroaryle, hétérocyclyle, cyano, NR13R14, OR13 ou un à cinq halo;
    (d) aryle, qui est optionnellement substitué par un à cinq halo;
    (e) hétéroaryle (où l'hétéroaryle a 5 ou 6 chaînons dans lesquels 1, 2, 3 ou 4 des atomes sont un hétéroatome sélectionné parmi N, S et O), lequel est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à cinq halo;
    (f) hétérocyclyle, qui est optionnellement substitué par (alkyle C1-6)OH ;
    R12 est sélectionné parmi le groupe consistant en:
    (a) hydrogène,
    (b) alkyle C1-6, qui est optionnellement substitué par aryle, hétéroaryle ou un à cinq halo;
    (c) cycloalkyle C3-6, qui est optionnellement substitué par aryle, hétéroaryle ou un à cinq halo;
    (d) aryle, qui est optionnellement substitué par un à cinq halo;
    (e) hétéroaryle (où l'hétéroaryle a 5 ou 6 chaînons dans lesquels 1, 2, 3 ou 4 des atomes sont un hétéroatome sélectionné parmi N, S et O), lequel est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à cinq halo;
    R13 est hydrogène ou alkyle C1-6 ;
    R14 est hydrogène ou alkyle C1-6 ;
    A est:
    (a) hydrogène;
    (b) alkyle C1-6, qui est optionnellement substitué par halo, hydroxyle, amino, phényle, hétérocyclyle, alkyle C1-6 ou R10 ;
    (c) alcényle C1-6, qui est optionnellement substitué par halo, hydroxyle, amino, phényle, hétérocyclyle, alkyle C1-6 ;
    (d) alcynyle C1-6, qui est optionnellement substitué par halo, hydroxyle, amino, phényle, hétérocyclyle, alkyle C1-6 ; ou
    (e) cycloalkyle C3-10, qui est optionnellement substitué par alkyle C1-6, OR13, NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, OR13 ou NR13R14), halo, R10 ou hétérocyclyle;
    (f) -(CO)R9 ;
    (g) -(CO)NR13R14 ;
    (h) hétérocyclyle C4-10, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par alkyle C1-6, halo, R10, -OR13, -NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, -OR13 ou -NR13R14), -(CO)R9 ou - (CO)NR13R14 ;
    (i) -OR13 ;
    (j) -NR13R14 ;
    (k) halo;
    (l) aryle, qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), O(alkyle C1-6), halo ou R10 ;
    (m) hétéroaryle, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), halo ou R10 ;
    (n) -O(aryle), qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6, halo ou R10 ; ou
    (o) -O(alkyle C1-6), qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6, halo ou R10 ;
    m est 0, 1 ou 2;
    n est 0, 1, 2 ou 3 ;
    ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci.
  2. Composé selon la revendication 1, dans lequel D est CH; E est CH; G est CH; J est CH ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci.
  3. Composé selon la revendication 1 ou 2, dans lequel
    R1 est
    (a) hydrogène;
    (b) halo;
    (c) aryle, qui est optionnellement substitué par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), -O(alkyle C1-6), halo ou R10 ;
    (d) hétéroaryle, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), halo ou R10 ;
    ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci.
  4. Composé selon la revendication 1 ou 2, dans lequel R1 est
    (a) alcynyle C1-6, qui est optionnellement substitué par un à deux substituants sélectionnés indépendamment parmi halo, hydroxyle, amino, phényle (qui est optionnellement substitué par alkyle C1-6), hétéroaryle (qui est optionnellement substitué par alkyle C1-6, O(alkyle C1-6), hétérocyclyle, alkyle C1-6, cycloalkyle C3-6, (C=O)NR13R14, NR13R14, Si(CH3)3;
    (b) -(C=O)NR13NR9,
    (c) hétérocyclyle C4-10, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par alkyle C1-6, halo, R10, -OR13, -NR13R14, phényle (qui est optionnellement substitué par alkyle C1-6, -OR14 ou NR13R14), -(C=O)R9 ou - (C=O)NR13R14 ;
    ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci.
  5. Composé selon l'une quelconque des revendications précédentes, dans lequel R2 est -NR5R6 ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci.
  6. Composé selon l'une quelconque des revendications précédentes, dans lequel R3 est hydrogène; halo ou hétéroaryle, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à trois groupes sélectionnés parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), halo ou R10- ; ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci.
  7. Composé selon la revendication 6, dans lequel R3 est halo ou hétéroaryle, qui est optionnellement substitué sur le carbone ou sur l'hétéroatome par un à trois groupes sélectionnés indépendamment parmi alkyle C1-6 (qui est optionnellement substitué par un à trois halo), halo ou R10 ; ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci.
  8. Composé selon la revendication 1, qui est
    9-bromo-6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2,6-difluorophényl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1 (2H)-one;
    6-[(2,2-diméthylpropyl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1 (2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-(pyridin-3-ylamino)benzo[c]-1,6-naphtyridin-1(2H)-one ;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(1,3-thiazol-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    6-(cyclobutylamino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1S)-1,2-diméthylpropyl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-1,2-diméthylpropyl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-(isopropylamino)benzo[c]-1,6-naphtyridin-1 (2H)-one;
    6-{[2-(diméthylamino)éthyl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[1-(2,4-dichloro-5-fluorophényl)éthyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one ;
    6-{[3-(diméthylamino)-2,2-diméthylpropyl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-(isobutylamino)benzo[c]-1,6-naphtyridin-1 (2H)-one;
    6-[(2,6-dichlorobenzyl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(3-hydroxy-2,2-diméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one ;
    9-fluoro-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(3-fluoropyridin-2-yl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one ;
    6-[(3,3-difluorocyclobutyl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(cyclopropylamino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one ;
    6-(cyclopropylamino)-9-bromobenzo[c]-1,6-naphtyridin-1(2H)-one ;
    9-fluoro-6-[isobutyl(3-morpholin-4-ylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one ;
    9-fluoro-6-[(1,7,7-triméthylbicyclo[2.2.1]hept-2-yl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(3,5-diméthylphényl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one ;
    9-fluoro-6-[(1-méthyl-2-pyridin-2-yléthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1S)-1-phényléthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2,2-difluoro-1-phényléthyl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(3-fluorophényl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(4-fluorophényl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(biphényl-2-ylamino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[1-(2-fluorophényl)éthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[1-(3,5-difluorophényl)éthyl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(3R)-1-benzylpipéridin-3-yl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(2,2,6,6-tétraméthylpipéridin-4-yl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1R)-1-phényléthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2-adamantylméthyl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(biphényl-3-ylamino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1R)-2,2,2-trifluoro-1-phényléthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1S)-2,2,2-trifluoro-1-phényléthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(4-méthoxybenzyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[1-(3-fluorophényl)éthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(1-phénylcyclopropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[cyclopropyl(1-méthylpipéridin-4-yl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[1-(hydroxyméthyl)cyclopropyl]aminolbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1-phénylcyclopentyl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1,1-dioxidotétrahydro-3-thiényl)méthyl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[2-fluoro-6-(trifluorométhyl)phényl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-{[(1S)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-{[(1R)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(4-chloro-2,6-difluorophényl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-(éthylamino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-anilino-9-bromobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-{[1-(2-chlorophényl)-2,2,2-trifluoroéthyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1S)-2-méthyl-1-(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2-chloro-4,6-difluorophényl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2,6-dichlorophényl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-1-(2,6-dichlorophényl)éthyl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1R)-1-(2-naphtyl)éthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[2,2,2-trifluoro-1-(2-fluorophényl)éthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(5-fluoro-2-hydroxyphényl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[3-fluoro-5-(pyridin-3-yloxy)phényl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[3-(1,3-thiazol-4-yl)phényl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(1,2,2-triméthylpropyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-6-[(2,4,6-trifluorophényl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[[3-(diméthylamino)propyl](pyridin-2-ylméthyl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2,2,2-trifluoroéthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[(2,2,2-trifluoro-1,1-diméthyléthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-6-[(2,4,6-trifluorophényl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(triméthylsilyl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[2,2,2-trifluoro-1-(2-furyl)éthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    trans-9-fluoro-6-[(3-méthylpipéridin-4-yl)amino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(3S)-pipéridin-3-ylamino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(3-thiénylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(pyridin-4-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(5-méthylisoxazol-3-yl)méthyl]amino}-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(pyridazin-3-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(benzylamino)-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(pyridin-3-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2-furylméthyl)amino]-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-phényl-6-[(pyridin-3-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(2-pyridin-4-yléthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(éthylamino)-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(3-thiénylméthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-[(3-hydroxypropyl)amino]-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-(pyridin-2-ylamino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(1,3-thiazol-2-ylméthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-({[9-(1-méthyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl]amino}méthyl)benzonitrile;
    9-phényl-6-(pyridin-3-ylamino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(1,2,2-triméthylpropyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-{[2-(méthylsulfonyl)éthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-(pyridin-4-ylamino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(11-méthyl-1H-pyrazol-4-yl)-6-{[(1-méthyl-1H-pyrazol-4-yl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    N-[9-(1-méthyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl]-bêta-alanine;
    3-{[9-(1-méthyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl]amino}propanenitrile;
    6-[(pyridin-2-ylméthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-{[(5-méthylisoxazol-3-yl)méthyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-[(3-aminopropyl)amino]-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    tert-butyl (3S)-3-[(1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphtyridin-6-yl)amino]pipéridine-1-carboxylate;
    9-fluoro-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-{[(1R)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-{[(1S)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2,4-diméthoxybenzyl)amino]-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    tert-butyl-trans-3-fluoro-4-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridine-1-carboxylate;
    9-bromo-6-{[(1-méthyl-1H-pyrazol-3-yl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(3-méthyl-3H-imidazol-4-ylméthyl)-amino]-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-[(pyrimidin-2-ylméthyl)-amino]-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-[(pyrazin-2-ylméthyl)-amino]-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-[(isoxazol-5-ylméthyl)-amino]-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-[(2-méthyl-2H-pyrazol-3-ylméthyl)-amino]-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-(1-pyridin-2-yl-éthylamino)-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-[(1H-pyrazol-3-ylméthyl)-amino]-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-[(pyrimidin-5-ylméthyl)-amino]-2H-benzo[c][1,6]naphtyridin-1-one;
    9-bromo-6-[(1-méthyl-1H-imidazol-2-ylméthyl)-amino]-2H-benzo[c] [1,6]naphtyridin-1-one;
    6-(benzylamino)pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-(méthylamino)pyrido [4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-(diméthylamino)pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-(benzylamino)pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-1,2,2-triméthylpropyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1S)-1,2,2-triméthylpropyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    3-{(3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridin-1-yl}-3-oxopropanenitrile;
    3-(3S)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridin-1-yl}-3-oxopropanenitrile;
    9-fluoro-6-(pipéridin-4-ylamino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{4-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridin-1-yl}-3-oxopropanenitrile;
    3-{(3S,4S)-3-fluoro-4-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridin-1-yl}-3-oxopropanenitrile;
    9-fluoro-6-{[(3R,4S)-3-fluoropipéridin-4-yl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{(3R,4S)-3-fluoro-4-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridin-1-yl}-3-oxopropanenitrile;
    3-{(1R,5S)-6-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]-3-azabicyclo[3.1.0]hex-3-yl}-3-oxopropanenitrile;
    6-({(3R)-1-[(2,4-difluorophényl)acétyl]pipéridin-3-yl}amino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(8-azabicyclo[3.2.1]oct-3-ylamino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-ftuoro-6-({(3R)-1-[(4-méthylmorpholin-2-yl)carbonyl]pipéridin-3-yl}amino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-{(3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridin-1-yl}-4-oxobutane-1-sulfonamide;
    6-{[(3R)-1-(N,N-diméthyl-b-alanyl)pipéridin-3-yl]amino}-9-fluorobenzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-fluoro-6-({(3R)-1-[3-(2-oxopyrrolidin-1-yl)propanoyl]pipéridin-3-yl} amino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-({(3R)-1-[(1,1-dioxidotétrahydro-3-thiényl)carbonyl]pipéridin-3-yl}amino)-9-fluorobenzo[c]-1,6-naphtyridin-1 (2H)-one;
    3-(3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]-8-azabicyclo[3.2.1]oct-8-yl}-3-oxopropanenitrile;
    9-fluoro-6-{[(3R)-1-(2-thiénylcarbonyl)pipéridin-3-yl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-([(3R)-1-(2,6-dichlorobenzoyl)pipéridin-3-yl]amino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-({(3R)-1-[(1-hydroxycyclopropyl)carbonyl]pipéridin-3-yl}amino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-({(3R)-1-[(1-méthylpipéridin-4-yl)carbonyl]pipéridin-3-yl} amino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-({(3R)-1-[(5-amino-4H-1,2,4-triazol-3-yl)carbonyl]pipéridin-3-yl}amino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-({(3R)-1-[(4,4-difluorocyclohexyl)carbonyl]pipéridin-3-yl}amino)-9-fluorobenzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-fluoro-6-{[(3R)-1-(pyrimidin-4-ylcarbonyl)pipéridin-3-yl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-[((3R)-1-{[1-(trifluorométhyl)cyclobutyl]carbonyl}pipéridin-3-yl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(3R)-1-(isoquinolin-8-ylcarbonyl)pipéridin-3-yl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    N-(3-{(3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridin-1-yl}-3-oxopropyl)acétamide;
    9-fluoro-6-({(3R)-1-[(1-méthyl-1H-pyrazol-4-yl)carbonyl]pipéridin-3-yl}amino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-({(3R)-1-[(3,3-difluorocyclobutyl)carbonyl]pipéridin-3-yl}amino)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-{[(3R)-1-(tétrahydro-2H-pyran-4-ylcarbonyl)pipéridin-3 - yl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-({(3R)-1-[(5-oxopyrrolidin-3-yl)carbonyl]pipéridin-3-yl}amino)benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{(3R)-3-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pyrrolidin-1-yl}-3-oxopropanenitrile;
    6-{[(1R)-1,2-diméthylpropyl]amino}-9-fluoro-4-(3-thiényl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-4-(1H-pyrazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-4-(4-méthoxyphényl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-4-(1H-pyrazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-4-(1H-indol-3-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-4-(1-méthyl-1H-pyrazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-chloro-6-{[(1R)-2-méthyl-1-(triftuorométhyl)propyl]amino}-4-(1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(1-cydopropyléthyl)amino]-9-fluoro-4-(1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-2-méthyl-1-(triftuorométhyl)propyl]amino}-9-(1H-pyrazol-5-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(cyclopropylamino)-9-(1H-pyrazol-5-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(cyclopropylamino)-9-phénylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(cyclopropylamino)-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(cyclopropylamino)-9-(1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-9-(1H-pyrrol-2-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    N-(2-cyanoéthyl)-4-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)benzamide;
    9-(1H-pyrazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1H-pyrazol-5-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1H-indol-2-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    N-[2-(diméthylamino)éthyl]-4-(6-[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)benzamide;
    4-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)-N-(2-morpholin-4-yléthyl)benzamide;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-9-(1H-pyrazol-5-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    N-(2-méthoxyéthyl)-4-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)benzamide;
    N-(2-cyanoéthyl)-4-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)benzamide;
    N-[2-(diméthylamino)éthyl]-3-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)benzamide;
    9-(4-{[4-(2-hydroxyéthyl)pipérazin-1-yl]carbonyl}phényl)-6-([(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-9-(4-morpholin-4-ylphényl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-[6-(hydroxyméthyl)pyridin-3-yl]-6-{(1R)-2-méthyl-1(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-imidazo[1,2-a]pyridin-6-yl-6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    2-fluoro-N-(2-hydroxyéthyl)-5-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)benzamide;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-9-[4-(morpholin-4-ylsulfonyl)phényl]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-[4-fluoro-3-(morpholin-4-ylcarbonyl)phényl]-6-{[(1R)-2-méthyl-1(trifluorométhyl)propyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-9-(6-morpholin-4-ylpyridin-3-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-9-[4-(morpholin-4-ylcarbonyl)phényl]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-nitro-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-iodo-6-[(1,2,2-triméthylpropyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(2-chloro-4,6-difluorophényl)amino]-4-iodobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-bromo-4-iodo-6-{[(1S)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(1R)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-[(3S)-pipéridin-3-ylamino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-(éthylamino)-4-iodobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-[(pyridazin-3-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-iodo-6-[(1,3-thiazol-2-ylméthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-iodo-6-[(2,2,2-trifluoroéthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-iodo-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    tert-butyl (3S)-3-[(4-iodo-1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphtyridin-6-yl)amino]pipéridine-1-carboxylate;
    4-iodo-6-[(pyridin-2-ylméthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    tert-butyl-trans-3-fluoro-4-[(9-fluoro-4-iodo-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridine-1-carboxylate;
    9-bromo-4-iodo-6-{[(3S)-1-(4-(diméthylamino)benzyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(4-(trifluorométhyl)benzyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-[(3S)-1-(propyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(méthylnaphtyridinyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(méthylcyclohexyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(éthyl)pipéridin-3-ylcarbonyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-[(3S)-1-(4-(diméthylamino)phényl)pipéridin-3-ylcarbonyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(3-(4-isopropylphényl)éthyl)pipéridin-3-ylcarbonyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-[(3S)-1-(2-pyridyl)pipéridin-3-yl carbonyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(méthyl)pipéridin-3-ylcarbonyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(méthanesulfonyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(éthanesulfonyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(cyclopropylsulfonyl)pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{([(3S)-1-(2-(thiophénylsulfonyl))pipéridin-3-yl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-([(3S)-1-(propylamino)pipéridin-3-ylcarbonyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{([(3S)-1-(tert-butylamino)pipéridin-3-ylcarbonyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-([(3S)-1-(4-fluorophényl)pipéridin-3-ylcarbonyl]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-([(35)-1-(4-méthoxybenzyl)pipéàdin-3-ylcarbonyl]amino)-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(méthyl)pipéridin-3-ylcarboxylate]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(éthyl)pipéridin-3-ylcarboxylate]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(phényl)pipéridin-3-ylcarboxylate]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-iodo-6-{[(3S)-1-(isobutyl)pipéridin-3-ylcarboxylate]amino}-benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-1-oxo-6-[(1,2,2-triméthylpropyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridine-4-carbonitrile;
    9-bromo-4-(méthylsulfonyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)one;
    9-bromo-4-nitro-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[cyclopropyl(hydroxy)méthyl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[cyclopropyl(hydroxy)méthyl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-[9-bromo-6-(éthylamino)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    9-bromo-4-(cyclopropyléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(cyclopropyléthynyl)-6-[(3S)-pipéridin-3-ylamino]benzo[c]-1,6-naphtyridin-1(2H)one;
    9-bromo-4-(3-hydroxyprop-1-yn-1-yl)-6-[(3S)-pipéridin-3-ylamino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{9-bromo-1-oxo-6-[(3S)-pipéridin-3-ylamino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    9-bromo-4-[(3S)-3-hydroxybut-1-yn-1-yl]-6-[(3S)-pipéridin-3-ylamino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(3R)-3-hydroxybut-1-yn-1-yl]-6-[(3S)-pipéridin-3-ylamino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(3S)-pipéridin-3-ylamino]-4-(pyridin-4-yléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-[9-bromo-6-(éthylamino)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    9-bromo-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}-4-(pyridin-2-yléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(cyclopropyléthynyl)-6-{[(3S)-1-(méthylsulfonyl)pipéridin-3-yl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(3R)-3-hydroxybut-1-yn-1-yl]-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}benzo[c]-1,6-naphtyridin-(2H)-one;
    9-bromo-6-[(3S)-pipéridin-3-ylamino]-4-(pyridin-2-yléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(1-méthyl-1H-imidazol-5-yl)éthynyl]-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}-4-(pyridin-3 - yléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(3S)-3-hydroxybut-1-yn-1-yl]-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-{[(3S)-1-(méthylsulfonyl)pipéridin-3-yl]amino}-4-(pyridin-3-yléthynyl)benzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-bromo-6-{[(3S)-1-(méthylsulfonyl)pipéridin-3-yl]amino}-4-(pyridin-4-yléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-{[(3S)-1-(méthylsulfonyl)pipéridin-3-yl]amino}-4-(pyridin-2-yléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(2-chloro-4,6-difluorophényl)amino]-4-(cyclopropyléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(2-chloro-4,6-difluorophényl)amino]-4-(pyridin-3-yléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(2-chloro-4,6-difluorophényl)amino]-4-(phényléthynyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(2-chloro-4,6-difluorophényl)amino]-4-[(triméthylsilyl)éthynyl]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(2-chloro-4,6-difluorophényl)amino]-4,9-bis[(triméthylsilyl)éthynyl]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-[(2-chloro-4,6-difluorophényl)amino]-4-[(triméthylsilyl)éthynyl]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(pyridin-3-yléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(pyridin-4-yléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(pyridin-2-yléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(3-hydroxyprop-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4,9-bis(3-hydroxyprop-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(3-aminoprop-1-yn-1-yl)-9-bromo-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(cyclohex-1-én-1-yléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(4-méthoxyphényl)éthynyl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-bromo-4-[(3-méthylphényl)éthynyl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4,9-bis(3-méthylbut-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4,9-bis(cyclohex-1-én-1-yléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(cyclohexyléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4,9-bis(3,3-diméthylbut-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(3,3-diméthylbut-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-bromo-4-[(2-méthylphényl)éthynyl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4,9-bis(4-méthylpent-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(3,3-diméthylbut-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4,9-bis[(3-méthylphényl)éthynyl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(1-méthyl-1H-imidazol-2-yl)éthynyl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-bromo-4-[(3S)-3-hydroxybut-1-yn-1-yl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    9-bromo-4-[(3R)-3-hydroxybut-1-yn-1-yl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-[(3R)-3-hydroxybut-1-yn-1-yl]-4-[(3S)-3-hydroxybut-1-yn-1-yl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(3S)-3-hydroxy-3-phénylprop-1-yn-1-yl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-[(3R)-3-hydroxy-3-phénylprop-1-yn-1-yl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(3-hydroxy-3-méthylbut-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4,9-bis(3-hydroxy-3-méthylbut-1-yn-1-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{9-bromo-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    9-bromo-4-(cyclopropyléthynyl)-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(pyridin-3-yléthynyl)-6-[(2,2,2-trifluoroéthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-(pyridin-3-yléthynyl)-6-[(1,2,2-triméthylpropyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(cyclopropyléthynyl)-6-[(pyridazin-3-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-6-[(1,2,2-triméthylpropyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-6-[(2,2,2-trifluoroéthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    tert-butyl (3S)-3-{[4-(cyclopropyléthynyl)-1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphtyridin-6-yl]amino}pipéridine-1-carboxylate;
    4-(cyclopropyléthynyl)-6-{[(5-méthylisoxazol-3-yl)méthyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-6-[(pyridin-2-ylméthyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-(pyridin-2-yléthynyl)-6-[(1,2,2-triméthylpropyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(cyclopropyléthynyl)-6-{[(1R)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(cyclopropyléthynyl)-6-{[(1S)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    tert-butyl-trans-4-{[4-(cyclopropyléthynyl)-9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl]amino}-3-fluoropipéridines-1-carboxylate;
    tert-butyl-trans-3-fluoro-4-[(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)amino]pipéridine-1-carboxylate;
    4-(cyclopropyléthynyl)-9-fluoro-6-[(trans-3-fluoropipéridin-4-yl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-6-[(3S)-pipéridin-3-ylamino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-9-(1H-pyrazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-(2H)-one;
    4-(cyclopropyléthynyl)-9-(1H-pyrazol-4-yl)-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-(2H)-one;
    4-(cyclopropyléthynyl)-9-(1H-pyrazol-5-yl)-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-(2H)-one;
    3-{1-oxo-9-(1H-pyrazol-5-yl)-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    9-bromo-4-[(1-méthyl-1H-imidazol-5-yl)éthynyl]-6-[(3S)-pipéridin-3-ylamino]benzo[c]-1,6-naphtyridin-1 (2H)-one;
    3-[1-oxo-6-[(pyridin-2-yléthyl)amino]-9-(3-thiényl)-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-{9-[4-(éthylsulfonyl)phényl]-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-[6-(éthylamino)-1-oxo-9-(1H-pyrazol-5-yl)-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-{9-[4-(cyanométhyl)phényl]-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(4-méthoxyphényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(1-méthyl-1H-pyrazol-4-yl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{6-(éthylamino)-9-[4-(1-morpholin-4-yléthyl)phényl]-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-[3-(hydroxyméthyl)phényl]-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(6-méthoxpyridin-3-yl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-[6-(éthylamino)-1-oxo-9-(3-thiényl)-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-[1-oxo-6-[(pyridin-2-ylméthyl)amino]-9-(2-thiényl)-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-{9-(3-hydroxyphényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-[4-(méthylsulfonyl)phényl]-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{ 9-(1H-indol-6-yl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{6-(éthylamino)-9-[4-(méthylsulfonyl)phényl]-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(5-méthyl-2-thiényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(2-hydroxyphényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{(9-(1,3-benzodioxol-5-yl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-[6-(éthylamino)-9-(3-hydroxyphényl)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-{6-(éthylamino)-1-oxo-9-[3-(1-pyrrolidin-1-yléthyl)phényl]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{6-(éthylamino)-9-[3-(hydroxyméthyl)phényl]-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(3-méthoxyphényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-[9-(1,3-benzodioxol-5-yl)-6-(éthylamino)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-{9-(3-méthyl-2-thiényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(2-méthoxypyrimidin-5-yl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{9-(2,3-diméthoxyphényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-{1-oxo-6-[(pyridin-2-ylméthyl)amino]-9-[4-(trifluorométhoxy)phényl]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3-[9-(2,3-diméthoxyphényl)-6-(éthylamino)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-[6-(éthylamino)-9-(2-fluoro-3-méthoxyphényl)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    3-{9-(2-éthoxyphényl)-1-oxo-6-[(pyridin-2-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    3 -[9-(2-éthoxyphényl)-6-(éthylamino)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    4-(cyclopropyléthynyl)-9-[4-(méthylsulfonyl)phényl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-9-[4-(éthylsulfonyl)phényl]-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{1-oxo-9-(1H-pyrazol-5-yl)-6-[(pyridazin-3-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    4-(cyclopropyléthynyl)-9-(1H-pyrazol-5-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{9-(3-cyanophényl)-1-oxo-6-[(pyridazin-3-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    4-(cyclopropyléthynyl)-9-(1-méthyl-1H-pyrazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    3-{9-[4-(hydroxyméthyl)phényl]-1-oxo-6-[(pyridazin-3-ylméthyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl}prop-2-ynamide;
    4-(cyclopropyléthynyl)-9-(1-méthyl-1H-pyrazol-4-yl)-6-[(pyridazin-3-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-9-(6-méthoxypyridin-3-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1, 6-naphtyridin-1(2H)-one;
    9-(1H-pyrazol-4-yl)-6-{[(1R)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-9-(1H-pyrazol-4-yl)-6-{([(1R)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-9-(1H-pyrazol-4-yl)-6-{[(1S)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    4-(cyclopropyléthynyl)-6-{[(1R)-1,2,2-triméthylpropyl]amino}benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-1-oxo-6-[(1,2,2-triméthylpropyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridine-4-carboxamide;
    N'-acétyl-9-bromo-1-oxo-6-[(1,2,2-triméthylpropyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridine-4-carbohydrazide;
    9-bromo-N-méthyl-1-oxo-6-[(1,2,2-triméthylpropyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridine-4-carboxamide;
    9-bromo-N-méthyl-1-oxo-6-[(1,2,2-triméthylpropyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridine-4-carboxamide;
    9-bromo-N-cyclopropyl-1-oxo-6-[(1,2,2-triméthylpropyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridine-4-carboxamide;
    N-benzyl-9-bromo-1-oxo-6-[(1,2,2-triméthylpropyl)amino]-1,2-dihydrobenzo[c]-1,6-naphtyridine-4-carboxamide;
    6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one-9-oxyde;
    6-[(1,2,2-triméthylpropyl)amino]pyrido[4,3-c]-1,6-naphtyridin-1(2H)-one-9-oxyde;
    N-(9-fluoro-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-6-yl)pipéridine-1-sulfonamide;
    9-fluoro-6-(1H-indol-3-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(1-benzyl-1H-pyrazol-4-yl)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    N-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)nicotinamide;
    N-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)isonicotinamide;
    9-bromo-3-méthyl-6-[(pyridin-2-ylméthyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-[(1,2,2-triméthylpropyl)amino]-9-[(triméthylsilyl)éthynyl]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-éthynyl-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(phényléthynyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1H-1,2,3-triazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-benzyl-1H-1,2,3-triazol-4-yl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-isopropylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-méthylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-éthylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-(tétrahydro-2H-pyran-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-cyclobutylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-(3,3-difluorocyclobutyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-(2,2-diméthylpropyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-sec-butylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-6-(1,1-dioxidotétrahydro-2-thiényl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-isopropylpyrido[4,3-c]-1,6-naphtyridin-1(2H)-one;
    N-méthyl-1-(1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphtyridin-6-yl)-N-phénylméthanesulfonamide;
    6-isopropyl-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(1-méthyl-1H-pyrazol-4-yl)-6-(tétrahydro-2H-pyran-4-yl)benzo[c]-1,6-naphtyridin-1(2H)one;
    6-éthyl-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(3,3-difluorocyclobutyl)-9-(1-méthyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-isopropyl-9-(morpholin-4-ylméthyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-isopropylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-isopropyl-9-(pyrrolidin-1-ylméthyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-isopropyl-9-(morpholin-4-ylcarbonyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-6-isopropylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-isopropyl-N,N-diméthyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridine-9-carboxamide;
    6-isopropyl-1-oxo-N-[3-(2-oxoazépan-1-yl)propyl]-1,2-dihydrobenzo[c]-1,6-naphtyridine-9-carboxamide;
    6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridine-9-carboxamide;
    N-acétyl-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridine-9-carbohydrazide;
    6-isopropyl-9-(5-méthyl-1,3,4-oxadiazol-2-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-6-isopropylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    3-(9-bromo-6-isopropyl-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl)prop-2-ynamide;
    3-[6-isopropyl-9-(1-méthyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-4-yl]prop-2-ynamide;
    9-bromo-4-(pyridin-3-yléthynyl)-6-(tétrahydro-2H-pyran-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(pyridin-2-yléthynyl)-6-(tétrahydro-2H-pyran-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-bromo-4-(pyridin-4-yléthynyl)-6-(tétrahydro-2H-pyran-4-yl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-isopropoxybenzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(cyclopropylméthoxy)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-(2,2,2-trifluoroéthoxy)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-(2-méthoxyéthoxy)benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-hydroxy-6-isopropoxybenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-(méthylsulfonyl)-6-[(1,2,2-triméthylpropyl)amino]benzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-isopropénylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-isopropylbenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-(1-hydroxy-1-méthyléthyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    6-(1,2-dihydroxy-1-méthyléthyl)-9-fluorobenzo[c]-1,6-naphtyridin-1(2H)-one;
    9-fluoro-6-(1-méthyl-2-morpholin-4-yléthyl)benzo[c]-1,6-naphtyridin-1(2H)-one;
    N-(6-{[(1R)-2-méthyl-1-(trifluorométhyl)propyl]amino}-1-oxo-1,2-dihydrobenzo[c]-1,6-naphtyridin-9-yl)-2-morpholin-4-ylacétamide;
    ou un sel ou stéréoisomère pharmaceutiquement acceptable de ceux-ci.
  9. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 8 ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci et un véhicule pharmaceutiquement acceptable.
  10. Composé selon l'une quelconque des revendications 1 à 8 ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci, à utiliser en thérapie.
  11. Utilisation du composé selon l'une quelconque des revendications 1 à 8 ou d'un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci, dans la préparation d'un médicament pour le traitement ou la prévention de troubles myéloprolifératifs ou du 1 cancer.
  12. Composé selon l'une quelconque des revendications 1 à 8 ou un sel ou stéréoisomère pharmaceutiquement acceptable de celui-ci, à utiliser dans le traitement ou la prévention de troubles myéloprolifératifs ou du cancer.
EP08726699A 2007-03-13 2008-03-10 Inhibiteurs de janus kinases et/ou protéine kinase-1 dépendant de la 3-phosphoinositide Active EP2134346B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90675307P 2007-03-13 2007-03-13
PCT/US2008/003206 WO2008112217A1 (fr) 2007-03-13 2008-03-10 Inhibiteurs de janus kinases et/ou protéine kinase-1 dépendant de la 3-phosphoinositide

Publications (3)

Publication Number Publication Date
EP2134346A1 EP2134346A1 (fr) 2009-12-23
EP2134346A4 EP2134346A4 (fr) 2010-07-21
EP2134346B1 true EP2134346B1 (fr) 2011-09-21

Family

ID=39759836

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08726699A Active EP2134346B1 (fr) 2007-03-13 2008-03-10 Inhibiteurs de janus kinases et/ou protéine kinase-1 dépendant de la 3-phosphoinositide

Country Status (7)

Country Link
US (1) US8329722B2 (fr)
EP (1) EP2134346B1 (fr)
JP (1) JP2010521459A (fr)
AT (1) ATE525375T1 (fr)
AU (1) AU2008226844A1 (fr)
CA (1) CA2679694A1 (fr)
WO (1) WO2008112217A1 (fr)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2698256A1 (fr) * 2007-09-11 2009-03-19 Merck Sharp & Dohme Corp. Inhibiteurs de janus kinases
JP5489296B2 (ja) * 2007-12-13 2014-05-14 メルク・シャープ・アンド・ドーム・コーポレーション Ｊａｎｕｓキナーゼの阻害剤
BRPI0821141A2 (pt) * 2007-12-21 2015-06-16 Hoffmann La Roche Derivados de heteroarila como antagonistas do receptor de orexina
WO2010144486A1 (fr) * 2009-06-08 2010-12-16 Takeda Pharmaceutical Company Limited Composés de dihydropyrrolonaphtyridinone comme inhibiteurs de jak
DE102010049877A1 (de) 2010-11-01 2012-05-03 Merck Patent Gmbh 7-((1,2,3)Triazol-4-yl)-pyrrolo(2,3) pyrazinderivate
WO2012085176A1 (fr) * 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Composés pyrazinones tricycliques, leurs compositions et leurs procédés d'utilisation en tant qu'inhibiteurs de janus kinase
DE102011008352A1 (de) 2011-01-12 2012-07-12 Merck Patent Gmbh 5-([1,2,3]Triazol-4-yl)-7H-pyrrolo-[2,3-d]pyrimidinderivate
DE102011009961A1 (de) 2011-02-01 2012-08-02 Merck Patent Gmbh 7-Azaindolderivate
US9199918B2 (en) 2011-02-15 2015-12-01 Georgetown University Small molecule inhibitors of AGBL2
WO2013123444A1 (fr) 2012-02-17 2013-08-22 Amgen Inc. Composés de sulfonyle qui interagissent avec la protéine régulatrice de la glucokinase
WO2014013014A1 (fr) 2012-07-18 2014-01-23 Fundació Privada Centre De Regulació Genòmica (Crg) Inhibiteurs de jak pour l'activation de populations de cellules souches épidermiques
DE102012019369A1 (de) 2012-10-02 2014-04-03 Merck Patent Gmbh 7-Azaindolderivat
WO2015146928A1 (fr) * 2014-03-24 2015-10-01 武田薬品工業株式会社 Composé hétérocyclique
WO2018041989A1 (fr) 2016-09-02 2018-03-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés de diagnostic et de traitement de la maladie coeliaque réfractaire de type 2
EP3898589A2 (fr) * 2018-12-21 2021-10-27 Saltigo GmbH Procédé de préparation de 2-alcoxy-4-amino-5-méthyl-pyridines et/ou de 2-alcoxy-4-alkylamino-5-méthyl-pyridines
EP3947737A2 (fr) 2019-04-02 2022-02-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes de prédiction et de prévention du cancer chez des patients ayant des lésions prémalignes
EP3955920A1 (fr) 2019-04-16 2022-02-23 Institut National de la Santé et de la Recherche Médicale (INSERM) Utilisation d'inhibiteurs de jak pour le traitement d'états douloureux impliquant des canaux nav1.7
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
WO2021257863A1 (fr) 2020-06-19 2021-12-23 Incyte Corporation Composés de pyrrolotriazine utilisés en tant qu'inhibiteurs de v617f de jak2
CA3188639A1 (fr) 2020-07-02 2022-01-06 Incyte Corporation Composes d'uree tricycliques en tant qu'inhibiteurs de v617f de jak2
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
WO2022046989A1 (fr) 2020-08-27 2022-03-03 Incyte Corporation Composés d'urée tricycliques en tant qu'inhibiteurs de v617f de jak2
WO2022140231A1 (fr) 2020-12-21 2022-06-30 Incyte Corporation Composés de déazaguanine utilisés en tant qu'inhibiteurs de v617f de jak2
CA3211748A1 (fr) 2021-02-25 2022-09-01 Incyte Corporation Lactames spirocycliques utilises comme inhibiteurs du v617f de jak2
WO2023222565A1 (fr) 2022-05-16 2023-11-23 Institut National de la Santé et de la Recherche Médicale Procédés d'évaluation de l'épuisement de cellules souches hématopoïétiques induites par une inflammation chronique
WO2024026128A2 (fr) * 2022-07-29 2024-02-01 Ensem Therapeutics, Inc. Dérivés aryle tricycliques, et compositions et procédés associés

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1826859A (en) * 1928-03-15 1931-10-13 Emil C Anderson Corrugated metallic wall plate
US2008640A (en) * 1934-03-17 1935-07-16 Nat Steel Car Corp Ltd Reenforced corrugated car ends
US2218688A (en) * 1938-04-21 1940-10-22 John W Stewart Ship construction
US2585980A (en) * 1946-06-26 1952-02-19 Vasta John Ship construction
US2741208A (en) * 1951-08-24 1956-04-10 Albiach Vincent Tank ship bulkhead and girder construction
US3110523A (en) * 1960-10-28 1963-11-12 Int Harvester Co Emergency releasing means for vehicle brakes
DE1450432B2 (de) * 1963-06-27 1976-01-08 Technigaz S.A., Paris Abwickelbare Dehnungswand tür einen Behälter
DE1501738C3 (de) * 1965-03-15 1974-05-22 Mcmullen, John Joseph, Montclair, N.J. (V.St.A.) Wärmeisolierter doppelwandiger Tank zur Lagerung oder zum Transport tiefsiedender verflüssigter Gase bei etwa atmosphärischem Druck
FR1554714A (fr) * 1967-10-12 1969-01-24
FR1568290A (fr) * 1968-03-26 1969-05-23
GB1302214A (fr) * 1970-03-19 1973-01-04 Conch Int Methane Ltd
GB1346771A (en) * 1970-05-20 1974-02-13 Hamilton W Low temperature cargo containers for ships
US3721362A (en) * 1970-09-09 1973-03-20 Mc Mullen J Ass Inc Double wall corrugated lng tank
US3811593A (en) * 1971-01-27 1974-05-21 Mc Millen J Ass Inc Double wall cargo tank having insulating secondary barrier
US3978808A (en) * 1973-09-11 1976-09-07 John J. Mcmullen Associates, Inc. Double wall cargo tank for transporting cryogenics
US3941272A (en) * 1974-03-27 1976-03-02 Kaiser Aluminum & Chemical Corporation Cryogenic transport
US4032608A (en) * 1974-07-12 1977-06-28 Kaiser Aluminum & Chemical Corporation Cryogenic liquid containment method
US3927788A (en) * 1974-07-12 1975-12-23 Kaiser Aluminium Chem Corp Cryogenic liquid containment system
US4116150A (en) * 1976-03-09 1978-09-26 Mcdonnell Douglas Corporation Cryogenic insulation system
US4207827A (en) * 1976-08-20 1980-06-17 Michel Gondouin System, tooling and method of construction of cryogenic tanks for LNG tankers and for LNG storage
US4101045A (en) * 1977-04-12 1978-07-18 Baltek Corporation Cryogenic container
DE3611920A1 (de) * 1986-04-09 1987-10-22 Vft Verkaufsges Teer Schiff fuer den fluessigtransport hochschmelzender aromatischer kohlenwasserstoffe
TW310306B (fr) * 1993-04-09 1997-07-11 Ishikawajima Harima Heavy Ind
TW242607B (fr) * 1993-05-27 1995-03-11 Ishikawajima Harima Heavy Ind
IL112249A (en) * 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
US5727492A (en) * 1996-09-16 1998-03-17 Marinex International Inc. Liquefied natural gas tank and containment system
NO983204L (no) * 1998-04-16 1999-10-18 Allied Applied Marine Technolo Bulk carrier
US7111750B2 (en) * 1998-10-15 2006-09-26 Exxonmobil Upstream Research Company Liquefied natural gas storage tank
US6732881B1 (en) * 1998-10-15 2004-05-11 Mobil Oil Corporation Liquefied gas storage tank
WO2001058899A1 (fr) 2000-02-09 2001-08-16 Novartis Ag Derives de pyridine inhibant l'angiogenese et/ou la tyrosine-kinase du recepteur de vegf
EP1303506B1 (fr) 2000-07-14 2005-02-02 ALTANA Pharma AG 6-heteroaryphenanthridines
US6626319B2 (en) * 2001-06-04 2003-09-30 Electric Boat Corporation Integrated tank erection and support carriage for a semi-membrane LNG tank
JP4286134B2 (ja) * 2001-08-01 2009-06-24 メルク エンド カムパニー インコーポレーテッド ベンズイミダゾ［４，５−ｆ］イソキノリノン誘導体
US6875780B2 (en) 2002-04-05 2005-04-05 Warner-Lambert Company Compounds that modulate PPAR activity and methods for their preparation
WO2005061519A1 (fr) * 2003-12-19 2005-07-07 Takeda San Diego, Inc. Inhibiteurs de kinase
US20060106020A1 (en) 2004-04-28 2006-05-18 Rodgers James D Tetracyclic inhibitors of Janus kinases
WO2007008502A2 (fr) * 2005-07-08 2007-01-18 Merck & Co., Inc. Inhibiteurs de kinases 'points de controle'

Also Published As

Publication number Publication date
AU2008226844A1 (en) 2008-09-18
WO2008112217A1 (fr) 2008-09-18
EP2134346A4 (fr) 2010-07-21
CA2679694A1 (fr) 2008-09-18
JP2010521459A (ja) 2010-06-24
ATE525375T1 (de) 2011-10-15
US8329722B2 (en) 2012-12-11
US20100160309A1 (en) 2010-06-24
EP2134346A1 (fr) 2009-12-23

Similar Documents

Publication Publication Date Title
EP2134346B1 (fr) Inhibiteurs de janus kinases et/ou protéine kinase-1 dépendant de la 3-phosphoinositide
EP2231143B1 (fr) 5H-pyrido[4,3-b]indoles comme iNHIBITEURS DE JANUS KINASES
EP2278969B1 (fr) Inhibiteurs de Janus kinases
EP2299816B1 (fr) Inhibiteurs de janus kinases
CA2703125C (fr) Pyrrolo[2,3-b]pyridines pyrazinyl-substituees, compositions a base de celles-ci et leur utilisation dans le traitement du cancer
EP1896421B1 (fr) Benzocycloheptapyridines comme inhibiteurs du recepteur tyrosine kinase met
EP2200612B1 (fr) Inhibiteurs de janus kinases
EP2341775B1 (fr) Inhibiteurs de janus kinases
EP2032141B1 (fr) Inhibiteurs de kinases janus
CA2630562A1 (fr) Composes tricycliques utilises comme inhibiteurs de kinases

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20091013

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: MERCK SHARP & DOHME CORP.

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20100621

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 471/04 20060101AFI20100615BHEP

Ipc: A61P 35/00 20060101ALI20100615BHEP

Ipc: C07D 471/14 20060101ALI20100615BHEP

Ipc: A61K 31/497 20060101ALI20100615BHEP

Ipc: A61K 31/00 20060101ALI20100615BHEP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 602008009983

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A61K0031497000

Ipc: C07D0471040000

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 35/00 20060101ALI20110307BHEP

Ipc: A61K 31/00 20060101ALI20110307BHEP

Ipc: A61K 31/497 20060101ALI20110307BHEP

Ipc: C07D 471/14 20060101ALI20110307BHEP

Ipc: C07D 471/04 20060101AFI20110307BHEP

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: SERVOPATENT GMBH

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602008009983

Country of ref document: DE

Effective date: 20111124

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20111221

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20110921

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20111222

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 525375

Country of ref document: AT

Kind code of ref document: T

Effective date: 20110921

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120121

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120123

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFUS

Owner name: SCHERING CORPORATION, US

Free format text: FORMER OWNER: MERCK SHARP DOHME CORP., US

Ref country code: CH

Ref legal event code: PFA

Owner name: MERCK SHARP & DOHME CORP.

Free format text: SCHERING CORPORATION#2000 GALLOPING HILL ROAD#KENILWORTH, NJ 07033 (US) -TRANSFER TO- MERCK SHARP & DOHME CORP.#126 EAST LINCOLN AVENUE#RAHWAY, NEW JERSEY 07065 (US)

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: SCHERING CORPORATION

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: MERCK SHARP & DOHME CORP.

26N No opposition filed

Effective date: 20120622

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20120802 AND 20120808

REG Reference to a national code

Ref country code: NL

Ref legal event code: SD

Effective date: 20120828

REG Reference to a national code

Ref country code: NL

Ref legal event code: TD

Effective date: 20120924

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602008009983

Country of ref document: DE

Effective date: 20120622

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120331

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120310

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 602008009983

Country of ref document: DE

Owner name: MERCK SHARP & DOHME CORP., US

Free format text: FORMER OWNER: MERCK SHARP & DOHME CORP., RAHWAY, US

Effective date: 20121213

Ref country code: DE

Ref legal event code: R082

Ref document number: 602008009983

Country of ref document: DE

Representative=s name: ABITZ & PARTNER, DE

Effective date: 20121213

Ref country code: DE

Ref legal event code: R081

Ref document number: 602008009983

Country of ref document: DE

Owner name: SCHERING CORPORATION, US

Free format text: FORMER OWNER: MERCK SHARP & DOHME CORP., RAHWAY, US

Effective date: 20121213

Ref country code: DE

Ref legal event code: R081

Ref document number: 602008009983

Country of ref document: DE

Owner name: MERCK SHARP & DOHME CORP., RAHWAY, US

Free format text: FORMER OWNER: MERCK SHARP & DOHME CORP., RAHWAY, N.J., US

Effective date: 20121213

Ref country code: DE

Ref legal event code: R082

Ref document number: 602008009983

Country of ref document: DE

Representative=s name: ABITZ & PARTNER PATENTANWAELTE MBB, DE

Effective date: 20121213

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

Owner name: SCHERING CORPORATION, US

Effective date: 20130318

Ref country code: FR

Ref legal event code: CD

Owner name: SCHERING CORPORATION, US

Effective date: 20130319

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120101

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20130129

Year of fee payment: 6

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 602008009983

Country of ref document: DE

Representative=s name: ABITZ & PARTNER, DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20111221

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 602008009983

Country of ref document: DE

Representative=s name: ABITZ & PARTNER, DE

Effective date: 20130514

Ref country code: DE

Ref legal event code: R081

Ref document number: 602008009983

Country of ref document: DE

Owner name: MERCK SHARP & DOHME CORP., US

Free format text: FORMER OWNER: SCHERING CORPORATION, RAHWAY, US

Effective date: 20130514

Ref country code: DE

Ref legal event code: R081

Ref document number: 602008009983

Country of ref document: DE

Owner name: MERCK SHARP & DOHME CORP., RAHWAY, US

Free format text: FORMER OWNER: SCHERING CORPORATION, RAHWAY, US

Effective date: 20130514

Ref country code: DE

Ref legal event code: R082

Ref document number: 602008009983

Country of ref document: DE

Representative=s name: ABITZ & PARTNER PATENTANWAELTE MBB, DE

Effective date: 20130514

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20130312

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20110921

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120310

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20080310

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20141001

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140331

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140331

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141001

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 602008009983

Country of ref document: DE

Owner name: MERCK SHARP & DOHME LLC, RAHWAY, US

Free format text: FORMER OWNER: MERCK SHARP & DOHME CORP., RAHWAY, N.J., US

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20220908 AND 20220914

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240209

Year of fee payment: 17

Ref country code: GB

Payment date: 20240208

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20240209

Year of fee payment: 17